Tricyclic indole derivatives and their use in the treatment of alzheimer&#39;s disease

ABSTRACT

The present invention to novel hydroxyethylamine compounds having Asp2 (β-secretase, BACE1 or Memapsin) inhibitory activit, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated β-amyloid levels or β-amyloid deposits, Particularly Alzheimer&#39;s disease.

The present invention relates to novel hydroxyethylamine compoundshaving Asp2 (β-secretase, BACE1 or Memapsin) inhibitory activity,processes for their preparation, to compositions containing them and totheir use in the treatment of diseases characterised by elevatedβ-amyloid levels or β-amyloid deposits, particularly Alzheimer'sdisease.

Alzheimer's disease is a degenerative brain disorder in whichextracellular deposition of Aβ in the form of senile plaques representsa key pathological hallmark of the disease (Selkoe, D. J. (2001)Physiological Reviews 81: 741-766). The presence of senile plaques isaccompanied by a prominent inflammatory response and neuronal loss.β-amyloid (Aβ) exists in soluble and insoluble, fibrillar forms and aspecific fibrillar form has been identified as the predominantneurotoxic species (Vassar, R. and Citron, M. (2000) Neuron 27:419-422). In addition it has been reported that dementia correlates moreclosely with the levels of soluble amyloid rather than plaque burden(Naslund, J. et al. (2000) J. Am. Med. Assoc. 12: 1571-1577; Younkin, S.(2001) Nat. Med. 1: 8-19). Aβ is known to be produced through thecleavage of the beta amyloid precursor protein (also known as APP) by anaspartyl protease enzyme known as Asp2 (also known as β-secretase, BACE1or Memapsin) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).

Therefore, it has been proposed that inhibition of the Asp2 enzyme wouldreduce the level of APP processing and consequently reduce the levels ofAβ peptides found within the brain. Therefore, it is also thought thatinhibition of the Asp2 enzyme would be an effective therapeutic targetin the treatment of Alzheimer's disease.

APP is cleaved by a variety of proteolytic enzymes (De Strooper, B. andKonig, G. (1999) Nature 402: 471-472). The key enzymes in theamyloidogenic pathway are Asp2 (β-secretase) and γ-secretase both ofwhich are aspartic proteinases and cleavage of APP by these enzymesgenerates Aβ. The non-amyloidogenic, α-secretase pathway, whichprecludes Aβ formation, has been shown to be catalysed by a number ofproteinases, the best candidate being ADAM10, a disintegrin andmetalloproteinase. Asp1 has been claimed to show both α- and β-secretaseactivity in vitro. The pattern of expression of Asp1 and Asp2 are quitedifferent, Asp2 is most highly expressed in the pancreas and brain whileAsp1 expression occurs in many other peripheral tissues. The Asp2knockout mouse indicates that lack of Asp2 abolished Aβ production andalso shows that in this animal model endogenous Asp1 cannot substitutefor the Asp2 deficiency (Luo, Y. et al. (2001) Nat Neurosci. 4: 231-232;Cai, H. et al. (2001) Nat Neurosci. 4: 233-234; Roberds, S. L. et al.(2001) Hum. Mol. Genet. 10: 1317-1324).

For an agent to be therapeutically useful in the treatment ofAlzheimer's disease it is preferable that said agent is a potentinhibitor of the Asp2 enzyme, but should ideally also be selective forAsp2 over other enzymes of the aspartyl proteinase family, e.g CathepsinD (Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes,Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic PressLondon. pp 828-836).

WO 01170672, WO 02/02512, WO 02/02505 and WO 02/02506 (ElanPharmaceuticals Inc.) describe a series of hydroxyethylamine compoundshaving β-secretase activity which are implicated to be useful in thetreatment of Alzheimer's disease.

We have found a novel series of compounds which are potent inhibitors ofthe Asp2 enzyme, thereby indicating the potential for these compounds tobe effective in the treatment of disease characterised by elevatedβ-amyloid levels or β-amyloid deposits, such as Alzheimer's disease.

Thus, according to a first aspect of the present invention we provide acompound of formula (I):

wherein

R¹ and R² independently represent C₁₋₃ alkyl, C₂₋₄ alkenyl, halogen,C₁₋₃ alkoxy, amino, cyano or hydroxy;

m and n independently represent 0, 1 or 2;

p represents 1 or 2;

A-B represents —NR⁵—SO₂— or —NR⁵—CO—;

R⁵ represents hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₈cycloalkyl, aryl, heteroaryl, arylC₁₋₆ alkyl-, heteroarylC₁₋₆ alkyl-,arylC₃₋₈ cycloalkyl- or heteroarylC₃₋₈ cycloalkyl-;

X—Y-Z represents —N—CR⁸═CR⁹—;

R⁸ represents hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl;

R⁹ represents hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl,arylC₁₋₆ alkyl-, heteroarylC₁₋₆ alkyl-, arylC₃₋₈ cycloalkyl-,heteroarylC₃₋₈ cycloalkyl-, —COOR¹⁰, —OR¹⁰, —CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹,—COC₁₋₆ alkyl or —SO₂C₁₋₆ alkyl (wherein R¹⁰ and R¹¹ independentlyrepresent hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl);

R³ represents optionally substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl, —C₁₋₆alkyl-heteroaryl or —C₁₋₆ alkyl-heterocyclyl;

R⁴ represents hydrogen, optionally substituted C₁₋₁₀ alkyl, C₂₋₆alkynyl, —C₃₋₈ cycloalkyl, —C₃₋₈ cycloalkenyl, aryl, heteroaryl,heterocyclyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₃₋₈ cycloalkyl-aryl,-heterocyclyl-aryl, —C₁₋₆ alkyl-aryl-heteroaryl,—C(R^(a)R^(b))—CONH—C₁₋₆ alkyl, —C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl,—C₁₋₆ alkyl-S—C₁₋₆ alkyl, —C₁₋₆ alkyl-NR^(c)R^(d), —C(R^(a)R^(b))—C₁₋₆alkyl, —C(R^(a)R^(b))-aryl, —C(R^(a)R^(b))-heteroaryl,—C(R^(a)R^(b))-heteroaryl-heteroaryl, —C(R^(a)R^(b))—C₁₋₆ alkyl-aryl,—C(R^(a)R^(b))—C₁₋₆ alkyl-heteroaryl, —C(R^(a)R^(b))—C₁₋₆alkyl-heterocyclyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl-aryl, —C₁₋₆ alkyl-O—C₁₋₆alkyl-heteroaryl or —C₁₋₆ alkyl-O—C₁₋₆ alkyl-heterocyclyl;

R^(a) and R^(b) independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl or C₃₋₈ cycloalkyl, or R^(a) and R^(b) togetherwith the carbon atom to which they are attached may form a C₃₋₈cycloalkyl or heterocyclyl group;

R^(c) and R^(d) independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl or R^(c) and R^(d) together withthe nitrogen atom to which they are attached may form a nitrogencontaining heterocyclyl group;

wherein said aryl, heteroaryl or heterocyclyl groups of R³—R⁵, R⁹ andR^(a)—R^(d) may be optionally substituted by one or more (eg. 1 to 5)C₁₋₆ alkyl, halogen, haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, oxo, C₁₋₆ alkoxy,C₂₋₆ alkynyl, C₂₋₆ alkenyl, amino, cyano, nitro, —NR²²COR²³,—CONR²²R²³—SO₂R²², —SO₂NR²²R²³, —COOR²², —C₁₋₆ alkyl-NR²²R²³ (whereinR²² and R²³ independently represent hydrogen, C₁₋₆ alkyl or C₃₋₈ mcycloalkyl), —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkanoyl or hydroxy groups;

and wherein said alkyl and cycloalkyl groups of R¹—R⁵, R⁸—R¹¹, R²²—R²³and R^(a)—R^(d) may be optionally substituted by one or more (eg. 1 to6) halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, amino, cyano,hydroxy, carboxy or —COOC₁₋₆ alkyl groups;

or a pharmaceutically acceptable salt or solvate thereof.

In one particular aspect of the present invention, there is provided acompound of formula (I) as defined above wherein:

p represents 2; and

R⁵ represents hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl,arylC₁₋₆ alkyl-, heteroarylC₁₋₆ alkyl, arylC₃₋₈ cycloalkyl orheteroarylC₃₋₈ cycloalkyl; and R³ represents optionally substituted C₁₋₆alkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl, —C₁₋₆alkyl-heteroaryl or —C₁₋₆ alkyl-heterocyclyl; and

R⁴ represents hydrogen, optionally substituted C₁₋₁₀ alkyl, —C₃₋₈cycloalkyl, —C₃₋₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, —C₃₋₈ cycloalkyl-aryl, -heterocyclyl-aryl, —C₁₋₆alkyl-aryl-heteroaryl, —C(R^(a)R^(b))—CONH—C₁₋₆ alkyl,—C(R^(a)R^(b))—C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, —C₁₋₆alkyl-NR^(c)R^(d), —C(R^(a)R^(b))—C₁₋₆ alkyl, —C(R^(a)R^(b))—aryl,—C(R^(a)R^(b))—C₁₋₆ alkyl-aryl, —C(R^(a)R^(b))—C₁₋₆ alkyl-heteroaryl,—C(R^(a)R^(b))—C₁₋₆ alkyl-heterocyclyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl-aryl,—C₁₋₆ alkyl-O—C₁₋₆ alkyl-heteroaryl or —C₁₋₆ alkyl-O—C₁₋₆alkyl-heterocyclyl; and

R^(a) and R^(b) independently represent hydrogen, C₁₋₆ alkyl, or R^(a)and R^(b) together with the carbon atom to which they are attached mayform a C₃₋₈ cycloalkyl or heterocyclyl group;

R^(c) and R^(d) independently represent hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, or R^(c) and R^(d) together with the nitrogen atom to whichthey are attached may form a heterocyclyl group;

optional substituents for alkyl and cycloalkyl groups of R³ and R⁴include one or more (eg. 1, 2 or 3) halogen, C₁₋₆ alkoxy, amino, cyanoor hydroxy groups;

and wherein said aryl, heteroaryl or heterocyclyl groups of R³, R⁴, R⁵and R⁹ may be optionally substituted by one or more (eg. 1, 2 or 3) C₁₋₆alkyl, halogen, —CF₃, —OCF₃, oxo, C₁₋₆ alkoxy, C₂₋₆ alkynyl, C₂₋₆alkenyl, amino, cyano, nitro, —NR²²COR²³, —CONR²²R²³—C₁₋₆ alkyl-NR²² R²³(wherein R²² and R²³ independently represent hydrogen, C₁₋₆ alkyl orC₃₋₈ cycloalkyl), —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkanoyl or hydroxygroups.

References to alkyl include references to both straight chain andbranched chain aliphatic isomers of the corresponding alkyl. It will beappreciated that references to alkenyl and alkynyl shall be interpretedsimilarly.

References to C₃₋₈ cycloalkyl include references to all alicyclic(including branched) isomers of the corresponding alkyl.

References to ‘aryl’ include references to monocyclic carbocyclicaromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings(e.g. naphthyl) or carbocyclic benzofused rings such as a C₃₋₈cycloalkyl fused to a phenyl ring (eg. dihydroindenyl).

References to ‘heteroaryl’ include references to mono- and bicyclicheterocyclic aromatic rings containing 1-4 hetero atoms selected fromnitrogen, oxygen and sulphur. Examples of monocyclic heterocyclicaromatic rings include but are not limited to e.g. thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl, pyridyl, tetrazolyl and the like. Examples ofbicyclic heterocyclic aromatic rings include eg. quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl,indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.

References to ‘heterocyclyl’ include references to a 5-7 memberednon-aromatic monocyclic ring containing 1 to 3 heteroatoms selected fromnitrogen, sulphur or oxygen. Examples of heterocyclic non-aromatic ringsinclude e.g. morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl,oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, dioxolanyl, oxathiolanyl,imidazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazolidinyland the like.

The term “nitrogen containing heterocyclyl” is intended to represent anyheterocyclyl group as defined above which contains a nitrogen atom.

Preferably, A-B represents —NR⁵—SO₂—.

Preferably, R⁵ represents hydrogen, C₁₋₆ alkyl (eg. methyl, ethyl ori-propyl) optionally substituted by one or more (eg. 1, 2 or 3) halogenatoms (eg. trifluoroethyl), carboxy (eg. —CH₂COOH) or —COOC₁₋₆ alkylgroups (eg. —CH₂—COO-t-Bu), aryl (eg. phenyl) or arylC₁₋₆ alkyl- (eg.benzyl). More preferably, R⁵ represents C₁₋₆ alkyl (eg. methyl or ethyl)or aryl (eg. phenyl), especially C₁₋₆ alkyl (eg. methyl or ethyl).

Preferably, m represents 0 or 1, more preferably 0.

When present, R¹ is preferably C₁₋₃ alkyl (eg. methyl).

Preferably, n represents 0.

Preferably, p represents 2.

Preferably, R⁸ represents hydrogen.

Preferably, R⁹ represents hydrogen or C₁₋₆ alkyl (eg. methyl, ethyl,propyl or isopropyl), more preferably C₁₋₆ alkyl (eg. ethyl, propyl orisopropyl).

Preferably, R³ represents —C₁₋₆ alkyl-aryl (eg. benzyl) optionallysubstituted by one or two halogen atoms (eg. chlorine or fluorine). Forexample, R³ preferably represents unsubstituted benzyl, 3-chlorobenzyl,3-fluorobenzyl or 3,5-difluorobenzyl.

Preferably, R⁴ represents

-hydrogen;

—C₁₋₁₀ alkyl (eg. methyl, ethyl, i-propyl, propyl, methylpropyl,dimethylethyl, butyl, 1,5-dimethylhexyl or 1,1,5-trimethylhexyl)optionally substituted by one or more halogen (eg. fluoroethyl,difluoroethyl or pentafluoropropyl) or C₁₋₆ alkoxy (eg. methoxy) groups;

C₂₋₆ alkynyl (eg. propynyl);

—C₃₋₈ cycloalkyl (eg. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl) optionally substituted by one or more halogen atoms (eg.fluorine) or C₁₋₆ alkyl groups (eg. methyl);

—C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl);

aryl (eg. dihydroindenyl);

-heterocyclyl (eg. tetrahydropyranyl);

—C(R^(a)R^(b))-aryl (eg. benzyl, 1-methyl-1-phenylethyl orα,α-dimethylbenzyl) optionally substituted (eg. substituted at the 3 and5 positions) by one or more halogen, cyano, nitro, haloC₁₋₆ alkyl (eg.—CF₃), haloC₁₋₆ alkoxy (eg. —OCF₃), C₁₋₆ alkyl (eg. methyl) or C₁₋₆alkoxy (eg. methoxy), C₂₋₆ alkynyl, C₂₋₆ alkenyl, amino, —NR²²COR²³,—CONR²²R²³ —SO₂R²², —SO₂NR²²R²³, —COOR²², —C₁₋₆ alkyl-NR²²R²³, —C₁₋₆alkanoyl or hydroxy groups;

—C(R^(a)R^(b))-heteroaryl (eg. —CH₂-pyrazolyl, —CH₂-pyridinyl,—CH₂-quinoxalinyl, —CH₂-quinolinyl, —CH₂-thienyl, —CH₂-pyrazinyl or—CH₂-isoxazolyl) optionally substituted by one or more C₁₋₆ alkyl (eg.methyl or ethyl), halogen (eg. bromine), haloC₁₋₆ alkyl (eg.trifluoroethyl) or —CONR²²R²³ (eg. —CONHMe) groups;

—C(R^(a)R^(b))-heteroaryl-heteroaryl (eg. —CH₂-pyridinyl-pyridinyl);

—C(R^(a)R^(b))—C₁₋₆ alkyl-aryl (eg. —(CH₂)₂-phenyl);

—C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl (eg. C(R^(a)R^(b))—CONH-cyclohexyl);or —C₃₋₈ cycloalkyl-aryl.

More preferably, R⁴ represents

—C₁₋₁₀ alkyl (eg. methyl, ethyl, i-propyl, propyl, methylpropyl,dimethylethyl, butyl, 1,5-dimethylhexyl or 1,1,5-trimethylhexyl)optionally substituted by one or more halogen (eg. fluoroethyl,difluoroethyl or pentafluoropropyl) or C₁₋₆ alkoxy (eg. methoxy) groups;

—C₃₋₈ cycloalkyl (eg. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl) optionally substituted by one or more halogen atoms (eg.fluorine) or C₁₋₆ alkyl groups (eg. methyl);

aryl (eg. dihydroindenyl);

-heterocyclyl (eg. tetrahydropyranyl);

—C(R^(a)R^(b))-aryl (eg. benzyl, 1-methyl-1-phenylethyl orα,α-dimethylbenzyl) optionally substituted (eg. substituted at the 3 and5 positions) by one or more halogen, cyano, haloC₁₋₆ alkyl (eg. —CF₃),haloC₁₋₆ alkoxy (eg. —OCF₃), C₁₋₆ alkyl (eg. methyl) or C₁₋₆ alkoxy (eg.methoxy) groups;

—C(R^(a)R^(b))-heteroaryl (eg. —CH₂-pyrazolyl, —CH₂-pyridinyl,—CH₂-quinoxalinyl, —CH₂-quinolinyl, —CH₂-thienyl, —CH₂-pyrazinyl or—CH₂-isoxazolyl) optionally substituted by one or more C₁₋₆ alkyl (eg.methyl or ethyl), halogen (eg. bromine), haloC₁₋₆ alkyl (eg.trifluoroethyl) or —CONR²²R²³ (eg. —CONHMe) groups; or

—C(R^(a)R^(b))—CONH—C₃₋₆ cycloalkyl (eg. C(R^(a)R^(b))—CONH-cyclohexyl).

Most preferably, R⁴ represents

—C₁₋₁₀ alkyl (eg. 1,1,5-trimethylhexyl);

—C₃₋₈ cycloalkyl (eg. cyclopropyl or cyclohexyl) optionally substitutedby one or more halogen atoms (eg. fluorine) or C₁₋₆ alkyl groups (eg.methyl);

aryl (eg. dihydroindenyl);

-heterocyclyl (eg. tetrahydropyranyl);

—C(R^(a)R^(b))-aryl (eg. benzyl or 1,1-dimethyl-phenyl) optionallysubstituted (eg. substituted at the 3 and 5 positions) by one or morehaloC₁₋₆ alkyl (eg. —CF₃), haloC₁₋₆ alkoxy (eg. —OCF₃), C₁₋₆ alkyl (eg.methyl) or C₁₋₆ alkoxy (eg. methoxy) groups;

—C(R^(a)R^(b))-heteroaryl (eg. —CH₂-pyrazolyl, —CH₂-pyridinyl,—CH₂-thienyl or —CH₂-isoxazolyl) optionally substituted by one or moreC₁₋₆ alkyl (eg. ethyl), haloC₁₋₆ alkyl (eg. trifluoroethyl) or—CONR²²R²³ (eg. —CONHMe) groups; or

—C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl (eg. C(R^(a)R^(b))—CONH-cyclohexyl).

Especially preferably, R⁴ represents

—C₃₋₈ cycloalkyl (eg. cyclopropyl or cyclohexyl) optionally substitutedby one or more halogen atoms (eg. fluorine);

-heterocyclyl (eg. tetrahydropyranyl);

—C(R^(a)R^(b))-aryl (eg. benzyl) optionally substituted (eg. substitutedat the 3 and 5 positions) by one or more haloC₁₋₆ alkyl (eg. —CF₃),haloC₁₋₆ alkoxy (eg. —OCF₃), C₁₋₆ alkyl (eg. methyl) or C₁₋₆ alkoxy (eg.methoxy) groups;

—C(R^(a)R^(b))-heteroaryl (eg. —CH₂-pyrazolyl, —CH₂-pyridinyl,—CH₂-thienyl or —CH₂-isoxazolyl) optionally substituted by one or moreC₁₋₆ alkyl (eg. ethyl), haloC₁₋₆ alkyl (eg. trifluoroethyl) or—CONR²²R²³ (eg. —CONHMe) groups; or

—C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl (eg. C(R^(a)R^(b))—CONH-cyclohexyl).

Preferably, R^(a) and R^(b) independently represent hydrogen or methyl,or R^(a) and R^(b) together with the carbon atom to which they areattached form a cyclopropyl or cyclohexyl group. More preferably R^(a)and R^(b) both represent hydrogen, both represent methyl or togetherwith the carbon atom to which they are attached form a cyclopropylgroup.

Preferred compounds according to the invention includes examples E1-E106as shown below, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic or organic acids e.g.hydrochlorides, hydrobromides, sulphates, phosphates, acetates,benzoates, citrates, nitrates, succinates, lactates, tartrates,fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates,methanesulphonates, p-toluenesulphonates, naphthalenesulphonates,formates or trifluoroacetates. The present invention includes within itsscope all possible stoichiometric and non-stoichiometric forms.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be solvated,eg. as the hydrate. This invention includes within its scopestoichiometric solvates (eg. hydrates) as well as compounds containingvariable amounts of solvent (eg. water).

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers) and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof. Preferably,compounds of formula (I) are in the form of a single enantiomer offormula (Ia):

The compounds of formula (I) and salts and solvates thereof may beprepared by the methodology described hereinafter, constituting afurther aspect of this invention.

A process according to the invention for preparing a compound of formula(I) which comprises:

(a) reacting a compound of formula (II)

or an activated and/or optionally protected derivative thereof whereinR¹, R², m, n, p, A, B, X, Y and Z are as defined above, with a compoundof formula (III)

wherein R³ and R⁴are as defined above; or

(b) preparing a compound of formula (I) which comprises reductivealkylation of a compound of formula (IV)

wherein R¹, R², R³, m, n, p, A, B, X, Y and Z are as defined above, withan appropriate aldehyde or ketone; or

(c) deprotecting a compound of formula (I) which is protected; andoptionally thereafter

(d) interconversion of compounds of formula (I) to other compounds offormula (I).

Process (a) typically comprises the use of water soluble carbodiimide,HOBT and a suitable base such as tertiary alkylamine or pyridine in asuitable solvent such as DMF and at a suitable temperature, eg. between0° C. and room temperature.

When process (a) utilises an activated derivative of the compound offormula (II), (eg. by activation of a carboxylic acid to an acidchloride, mixed anhydride, active ester, O-acyl-isourea or otherspecies), process (a) typically comprises treatment of said activatedderivative with an amine (Ogliaruso, M. A.; Wolfe, J. F. in TheChemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The Chemistryof Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp 442-8;Beckwith, A. L. J. in The Chemistry of Functional Groups (Ed. Patai, S.)Suppl. B: The Chemistry of Amides (Ed. Zabricky, J.) (John Wiley andSons, 1970), p 73 ff.

Process (b) typically comprises the use of sodium borohydride triacetatein the presence of a suitable solvent, such as ethanol, dichloromethaneand 1,2-dichloroethane and at a suitable temperature, e.g. between 0° C.and room temperature.

In process (c), examples of protecting groups and the means for theirremoval can be found in T. W. Greene and P. G. M. Wuts ‘ProtectiveGroups in Organic Synthesis’ (J. Wiley and Sons, 3rd Ed. 1999). Suitableamine protecting groups include aryl sulphonyl (e.g. tosyl), acyl (e.g.acetyl), carbamoyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) andarylalkyl (e.g. benzyl), which may be removed by hydrolysis orhydrogenolysis as appropriate. Other suitable amine protecting groupsinclude trifluoroacetyl (—COCF₃) which may be removed by base catalysedhydrolysis. Suitable hydroxy protecting groups would be silyl basedgroups such as t-butyldimethylsilyl, which may be removed using standardmethods, for example use of an acid such as trifluoroacetic orhydrochloric acid or a fluoride source such as tetra n-butylammoniumfluoride.

Process (d) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,aromatic substitution, ester hydrolysis, amide bond formation or removaland sulphonylation.

Compounds of formula (II) and/or activated and optionally protectedderivatives thereof may be prepared in accordance with the followingprocess:

wherein R¹, R², m, n, p, A, B, X, Y and Z are as defined above, P¹represents a suitable group such as C₁₋₆ alkyl, L¹ and L² independentlyrepresent a suitable leaving group such as a halogen atom (eg.chlorine).

When B represents CO, step (i) typically comprises the use of a suitablebase such as triethylamine in the presence of a suitable solvent such asdichloromethane at a suitable temperature, such as room temperature.

When B represents SO₂, step (i) typically comprises the use of asuitable base such as pyridine in the presence of a suitable reagent,eg. DMAP and a suitable solvent such as dichloromethane at a suitabletemperature, such as room temperature.

When B represents CO, step (ii) typically comprises the use of sodiumhydride in the presence of a suitable solvent, eg. dimethylformamide ata suitable temperature, eg. 100° C.

When B represents SO₂, step (ii) typically comprises the use of asuitable base such as triethylamine in the presence of a suitablesolvent such as dichloromethane at a suitable temperature, such as roomtemperature, followed by a subsequent reaction with sodium hydride inthe presence of a suitable solvent, eg. dimethylformamide at a suitabletemperature, eg. 100° C.

Step (iii) typically comprises a standard procedure for conversion of acarboxylic ester to an acid, such as the use of an appropriate alkalimetal hydroxide like lithium or sodium hydroxide in an appropriatesolvent such as methanol at an appropriate temperature such as roomtemperature. In the case of a tert-butyl ester this conversion can beachieved by the use of an appropriate acid such as trifluoroacetic acidin an appropriate solvent such as dichloromethane at an appropriatetemperature such as 0° C. Activated derivatives of compounds of formula(II) may then be prepared as described in process (a) above.

Compounds of formula (III) may be prepared in accordance with thefollowing process:

wherein R³ and R⁴ are as defined above and P² represents a suitableamine protecting group, such as t-butoxycarbonyl.

Step (i) typically comprises the reaction of a compound of formula(VIII) with a compound of formula NH₂R⁴ in the presence of a suitablesolvent, e.g. ethanol at a suitable temperature, e.g. reflux.

Step (ii) typically comprises the use of suitable deprotection reactionsas described above for process (c), eg. when P² representst-butoxycarbonyl, deprotection typically comprises the use oftrifluoroacetic acid in the presence of a suitable solvent, such asdichloromethane at a suitable temperature, e.g. between 0° C. and roomtemperature.

Compounds of formula (IV) may be prepared in accordance with thefollowing process:

wherein R¹, R², R³, m, n, p, A, B, X, Y, Z and P² are as defined aboveand P³ represents a suitable amine protecting group different to P²,such as —COOCH₂-phenyl.

Step (i) typically comprises the reaction of a compound of formula(VIII) in aqueous ammonia in the presence of a suitable solvent, e.g.ethanol at a suitable temperature, e.g. reflux.

When P³ represents —COOCH₂-phenyl, step (ii) typically comprises the useof ClCOOCH₂-phenyl in the presence of a suitable base, e.g.triethylamine, a suitable solvent, e.g. dimethylformamide at a suitabletemperature, e.g. between 0° C. and room temperature.

Step (iii) typically comprises the use of suitable deprotectionreactions as described above for process (c), eg. when P² representst-butoxycarbonyl, deprotection typically comprises the use oftrifluoroacetic acid in the presence of a suitable solvent, such asdichloromethane at a suitable temperature, e.g. between 0° C. and roomtemperature.

Step (iv) typically comprises reacting a compound of formula (XI) with acompound of formula (II) in the presence of water soluble carbodiimideand HOBT.

Step (v) typically comprises the use of suitable deprotection reactionsas described above for process (c), eg. when P³ represents—COOCH₂-phenyl, deprotection typically comprises the use of a suitablecatalyst, eg. palladium in the presence of a suitable solvent, e.g.water and ethanol and in the presence of a suitable hydrogen source,e.g. ammonium formate at a suitable temperature, eg. 60° C.

Compounds of formula (V) and (VII) are either commercially available ormay be prepared from commercially available compounds using standardprocedures.

As a further aspect of the invention there is thus provided a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereoffor use as a pharmaceutical, particularly in the treatment of patientswith diseases characterised by elevated β-amyloid levels or β-amyloiddeposits.

According to another aspect of the invention, there is provided the useof a compound of formula (I) or a physiologically acceptable salt orsolvate thereof for the manufacture of a medicament for the treatment ofpatients with diseases characterised by elevated β-amyloid levels orβ-amyloid deposits.

In a further or alternative aspect there is provided a method for thetreatment of a human or animal subject with diseases characterised byelevated β-amyloid levels or β-amyloid deposits, which method comprisesadministering to said human or animal subject an effective amount of acompound of formula (I) or a physiologically acceptable salt or solvatethereof.

As a further aspect of the invention there is thus provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in thetreatment of diseases characterised by elevated β-amyloid levels orβ-amyloid deposits.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment of diseasescharacterised by elevated β-amyloid levels or β-amyloid deposits.

The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions for use in thetherapy of diseases characterised by elevated β-amyloid levels orβ-amyloid deposits, comprising a compound of formula (I) or aphysiologically acceptable salt or solvate thereof together, ifdesirable, with one or more physiologically acceptable diluents orcarriers.

It will be appreciated that diseases characterised by elevated β-amyloidlevels or β-amyloid deposits include Alzheimer's disease, mild cognitiveimpairment, Down's syndrome, hereditary cerebral haemorrhage withβ-amyloidosis of the Dutch type, cerebral β-amyloid angiopathy andvarious types of degenerative dementias, such as those associated withParkinson's disease, progressive supranuclear palsy, cortical basaldegeneration and diffuse Lewis body type of Alzheimer's disease.

Most preferably, the disease characterised by elevated β-amyloid levelsor β-amyloid deposits is Alzheimer's disease.

There is also provided a process for preparing such a pharmaceuticalformulation which comprises mixing the ingredients.

Compounds of formula (I) may be used in combination with othertherapeutic agents. Suitable examples of such other therapeutic agentsmay be acetylcholine esterase inhibitors (such astetrahydroaminoacridine, donepezil hydrochloride and rivastigmine),gamma secretase inhibitors, anti-inflammatory agents (such ascyclooxygenase II inhibitors), antioxidants (such as Vitamin E andginkolidesor), statins or p-glycoprotein (P-gp) inhibitors (such ascyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS,ritonavir, megestrol acetate, progesterone, rapamycin,10,11-methanodibenzosuberane, phenothiazines, acridine derivatives suchas GF120918, FK506, VX-710, LY335979 and PSC-833).

When the compounds are used in combination with other therapeuticagents, the compounds may be administered either sequentially orsimultaneously by any convenient route.

The compounds according to the invention may, for example, be formulatedfor oral, inhaled, intranasal, buccal, enteral, parenteral, topical,sublingual, intrathecal or rectal administration, preferably for oraladministration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose,sugar, maize-starch, calcium phosphate or sorbitol; lubricants, forexample, magnesium stearate, stearic acid, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, croscarmellose sodiumor sodium starch glycollate; or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethyl cellulose, aluminium stearate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-oleate or acacia; non-aqueous vehicles (which may includeedible oils), for example almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; or preservatives, forexample, methyl or propyl p-hydroxybenzoates or sorbic acid. Thepreparations may also contain buffer salts, flavouring, colouring and/orsweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated forparenteral administration by bolus injection or continuous infusion andmay be presented in unit dose form, for instance as ampoules, vials,small volume infusions or pre-filled syringes, or in multi-dosecontainers with an added preservative. The compositions may take suchforms as solutions, suspensions, or emulsions in aqueous or non-aqueousvehicles, and may contain formulatory agents such as anti-oxidants,buffers, antimicrobial agents and/or tonicity adjusting agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water,before use. The dry solid presentation may be prepared by filling asterile powder aseptically into individual sterile containers or byfilling a sterile solution aseptically into each container andfreeze-drying.

When the compounds of the invention are administered topically they maybe presented as a cream, ointment or patch.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 3000 mg;and such unit doses may be administered more than once a day, forexample one, two, three or four times per day (preferably once ortwice); and such therapy may extend for a number of weeks, months oryears.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

Preparation of Intermediates

Description 1

Methyl 4-amino-3-nitrobenzoate (D1)

To a suspension of 4-amino-3-nitrobenzoic acid (50 g, 270 mmol, 1 equiv)in MeOH (600 ml) at room temperature was added SOCl₂ (20 ml, 270 mmol, 1equiv) dropwise. The resulting suspension was refluxed for 16 h thencooled to room temperature. The suspension was filtered off to givemethyl-4-amino-3-nitrobenzoate (D1) (53 g, 100%) as a yellow solid whichwas used in the next step without further purification. [M+H]⁺=197.3,RT=2.42 min.

Description 2

Methyl 4-amino-3-bromo-5-nitrobenzoate (D2)

To a solution of methyl-4-amino-3-nitrobenzoate (D1) (48 g, 244 mmol, 1equiv) in CH₂Cl₂ (1.4 l) at room temperature was added bromine (16.3 ml,318 mmol, 1.3 equiv). The resulting solution was refluxed for 2 h thenanother 6 ml (117 mmol, 0.5 equiv) of bromine were added and thesolution was stirred for 1 h then cooled to room temperature. Theorganic phase was washed twice with a 10% sodium thiosulfite aqueoussolution (200 ml) then with H₂O (200 ml), dried over MgSO₄ andconcentrated in vacuo to give methyl 4-amino-3-bromo-5-nitrobenzoate(D2) (66.2 g, 98%) as a yellow solid which was used in the next stepwithout further purification. [M−H]⁻=274.1, RT=2.90 min.

Description 3

Methyl 3-bromo-5-nitro-4-[(trifluoroacetyl)amino]benzoate (D3)

To a solution of methyl 4-amino-3-bromo-5-nitrobenzoate (D2) (66 g, 240mmol, 1 equiv) in CH₂Cl₂ (1.4 l) at 0° C. was added pyridine (100 ml,720 mmol, 3 equiv) then (CF₃CO)₂O (51 ml, 360 mmol, 1.5 equiv) and theresulting solution was stirred for 1 h. MeOH (29 ml, 720 mmol, 3 equiv)was added and the solution was stirred for 15 min. then concentrated invacuo. The residue was dissolved in AcOEt (350 ml) and the organic phasewas washed three times with a 2N aqueous HCl solution (200 ml). Thecombined aqueous phases were acidified to pH 1 with concentrated HCl andextracted with AcOEt. The combined organic phases were washed withbrine, a saturated NaHCO₃ aqueous solution and brine then dried overMgSO₄ and concentrated in vacuo to give methyl3-bromo-5-nitro-4-[(trifluoroacetyl)amino]benzoate (D3) (87.2 g, 93%) asa brown oil which was used in the next step without furtherpurification. [M+H]⁺=372.2, RT=2.92 min.

Description 4

Methyl3-bromo-4-[(2E/Z)-2-buten-1-yl(trifluoroacetyl)amino]-5-nitrobenzoate(D4)

To a solution of methyl3-bromo-5nitro-4-[(trifluoroacetyl)amino]benzoate (D3) (84.5 g, 228mmol, 1 equiv) in CH₃CN (1 l) at room temperature under nitrogen wasadded K₂CO₃ (37.7 g, 273 mmol, 1.2 equiv) and (2E/Z)-1-bromo-2-butene(30.5 ml, 296 mmol, 1.3 equiv) and the resulting suspension was refluxedfor 2 h. (2E/Z)-1-bromo-2-butene (5 ml, 48 mmol, 0.2 equiv) was thenadded and the suspension refluxed for another hour then cooled to roomtemperature. The precipitate was filtered off and washed with AcOET andthe organic phase concentrated in vacuo. The residue was dissolved inAcOEt and the organic phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo to give methyl3-bromo-4-[(2E/Z)-2-buten-1-yl(trifluoroacetyl)amino]-5-nitrobenzoate(D4) as a brown oil (95 g, 98%) which was used in the next step withoutfurther purification. RT=3.70 min.

Descriptions 5 and 6 (D5 and D6)

Descriptions 5 and 6 were obtained using an analogous procedure to thatdescribed for Description 4 (D4) from Description 3 (D3) using theappropriate allyl bromide indicated in the table below: Allyl RT Namebromide [M + H]⁺ (min.) Methyl 3-bromo-5-nitro-4-[(2E)- 2-penten-1-yl(trifluoroacetyl)amino]benzoate (D5)

— 3.80 Methyl 3-bromo-4-[(3-methyl-2-buten-1-yl)(trifluoroacetyl)amino]- 5-nitrobenzoate (D6)

— 3.46Description 7

Methyl 3-ethyl-7-nitro-1H-indole-5-carboxylate and methyl(3Z)-3-ethylidene-7-nitro-2,3-dihydro-1H-indole-5-carboxylate (D7)

To a flask charged with methyl3-bromo-4-[(2E/Z)-2-buten-1-yl(trifluoroacetyl)amino]-5-nitrobenzoate(D4) (11.1 g, 26.1 mmol, 1 equiv), NaCOOH (1.8 g, 26.1 mmol, 1 equiv),Na₂CO₃ (6.9 g, 65.3 mmol, 2.5 equiv), NBu₄Cl (8 g, 28.7 mmol, 1.1 equiv)and Pd(OAc)₂ (440 mg, 2.0 mmol, 0.075 equiv) at room temperature undernitrogen was added DMF (100 ml) and the resulting mixture was stirred at100° C. for 1 h then cooled to room temperature. The insoluble materialwas filtered off and washed with AcOEt and the combined organic phaseswere concentrated in vacuo. The residue was dissolved in AcOEt and thered precipitate formed (2.6 g) was filtered off. The organic phase waswashed with water and brine, dried over MgSO₄ and concentrated in vacuo.The residue was triturated with CH₂Cl₂ and the red precipitate formed(2.1 g) filtered off. The organic phase was concentrated in vacuo andthe residue (7 g, black oil) was purified by flash chromatography onsilica gel (iso-hexane/AcOEt: 6/4 then 1/1) to give methyl3-ethyl-7-nitro-1H-indole-5-carboxylate (D7) (1.56 g, 24%) as a pale redsolid. All red solids obtained (mixture of D7 and tetrabutyl ammoniumsalts) were washed with CH₃CN to give a mixture of methyl3-ethyl-7-nitro-1H-indole-5-carboxylate and methyl(3Z)-3-ethylidene-7-nitro-2,3-dihydro-1H-indole-5-carboxylate (D7) (3.36g, 52%) which were used in the next step without further purification.[M−H]⁻=247.2, RT=3.42 min.

Descriptions 8-9 (D8-D9)

Descriptions 8-9 were obtained using an analogous procedure to thatdescribed for Description 7 from the appropriate precursor indicated inthe table below: RT Name Precursor [M + H]⁺ (min.) Methyl7-nitro-3-propyl-1H-indole-5- D5 263.2 3.56 carboxylate (D8) Methyl3-(1-methylethyl)-7-nitro-1H- D6 indole-5-carboxylate (D9)Description 10

Methyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D10)

To a suspension of methyl 3-ethyl-7-nitro-1H-indole-5-carboxylate andmethyl (3Z)-3-ethylidene-7-nitro-2,3-dihydro-1H-indole-5-carboxylate(D7) (3.1 g, 12.5 mmol, 1 equiv) in toluene (150 ml) at room temperatureunder nitrogen was added palladium on charcoal (10% w/w and 50% wet, 620mg, 10% w/w) and the resulting suspension was stirred under anatmosphere of hydrogen (1 bar) for 24 h. The catalyst was filtered offthrough a pad of celite and washed copiously with AcOEt. Th combinedorganic phases were concentrated in vacuo to give methyl7-amino-3-ethyl-1H-indole-5-carboxylate (D10) (2.65 g, 97%) as a paleyellow solid which was used in the next step without furtherpurification. [M+H]⁺=219.4, RT=2.82 min.

Descriptions 11-12 (D11-D12)

Descriptions 11-12 (D11-D12) were obtained in an analogous manner tothat described for Description 10 from the appropriate precursorindicated in the table below: Name Precursor [M + H]⁺ RT (min.) Methyl7-amino-3-propyl-1H-indole- D8 233.2 3.06 5-carboxylate (D11) Methyl7-amino-3-(1-methylethyl)- D9 1H-indole-5-carboxylate (D12)Description 13

Methyl 7-[(ethenylsulfonyl)amino]-3-ethyl-1H-indole-5-carboxylate (D13)

To a solution of methyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D10)(2.15 g, 9.87 mmol, 1 equiv) in CH₂Cl₂ (70 ml) at room temperature wereadded pyridine (2 ml, 24.7 mmol, 2.5 equiv), DMAP (120 mg, 0.98 mmol,0.1 equiv) and 2-chloroethanesulfonyl chloride (1.24 ml, 11.8 mmol, 1.2equiv) and the resulting mixture was stirred for 12 h then diluted withAcOEt. The organic phase was washed with a 2N aqueous HCl solution,dried over MgSO₄ and concentrated in vacuo to give crude methyl7-[(ethenylsulfonyl)amino]-3-ethyl-1H-indole-5-carboxylate (D13) (2.98g, 98%) as a purple solid which was used in the next step withoutfurther purification. [M+H]⁺=309.1, RT=3.29 min.

Descriptions 14-15 (D14-D15)

Descriptions 14-15 (D14-D15) were obtained using an analogous manner tothat described for Description 13 from the appropriate precursorindicated in the table below: Name Precursor [M + H]⁺ RT (min.) Methyl7-[(ethenylsulfonyl)amino]- D11 323.4 2.983-propyl-1H-indole-5-carboxylate (D14) Methyl7-[(ethenylsulfonyl)amino]- D12 323.4 3.19 3(1-methylethyl)-1H-indole-5-carboxylate (D15)Description 16

Methyl 7-[(3-chloropropanoyl)amino]-3-ethyl-1H-indole-5-carboxylate(D16)

To a solution of methyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D10)(300 mg, 1.29 mmol, 1 equiv) in CH₂Cl₂ (10 ml) were added NEt₃ (216 μl,1.55 mmol, 1.2 equiv) and 3-chloropropionyl chloride (136 μl, 1.42 mmol,1.1 equiv) and the resulting solution was stirred at room temperaturefor 48 h then diluted with AcOEt and washed with H₂O. The organic phasewas dried over MgSO₄ and concentrated in vacuo. Purification of theresidue by flash chromatography on silica gel (iso-hexane/AcOEt: 3/1)gave methyl 7-[(3-chloropropanoyl)amino]-3-ethyl-1H-indole-5-carboxylate(D16) (300 mg, 72%) as a white solid. [M+H]⁺=309.4, RT=3.18 min.

Descriptions 17-18 (D17-D18)

Descriptions 17-18 (D17-D18) were obtained using an analogous procedureto that described for Ester 2 (B2) from the appropriate precursorindicated in the table below: Name Precursor [M + H]⁺ RT (min.) Methyl7-propyl-3,4-dihydro-1H- D14 323.2 2.94[1,2,5]thiadiazepino[3,4,5-hi]indole- 9-carboxylate 2,2-dioxide (D17)Methyl 7-(1-methylethyl)-3,4- D15 323.4 2.97 dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxylate 2,2-dioxide (D18)Description 19

1,1-Dimethylethyl[(1S,2R)-3-amino-2-hydroxy-1-(phenylmethyl)propyl]carbamate (D19)

To a solution of 1,1-dimethylethyl{(1S)-1-[(2S)-2-oxiranyl]-2-phenylethyl}carbamate (25 g, 95.1 mmol, 1equiv)) [Chirex 1819W94 Lot#9924382] in MeOH (350 ml) was added aqueousammonia (32% w/w, 180 ml, 3.2 mol, 3.3 equiv). The resulting mixture wasstirred at room temperature for 16 h then concentrated in vacuo to give1,1-dimethylethyl[(1S,2R)-3-amino-2-hydroxy-1-(phenylmethyl)propyl]carbamate (D19) (25.2g, 95%) as a white solid which was used in the next step without furtherpurification.

Description 20-25 (D20-D25)

Descriptions 20-25 were obtained using an analogous manner to thatdescribed for Example 1 (E1) from the appropriate acid and theappropriate amine indicated in the table below: Acid Amine DescriptionPrecursor Precursor [M + H]+ RT (min) Phenylmethyl ((2R,3S)-4-(3- A3 C50653.4 3.40 chlorophenyl)-3-{[(7-ethyl-1-methyl-2,2-dioxido-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indol-9-yl)carbonyl]amino}-2- hydroxybutyl)methylcarbamate (D20) Phenylmethyl[(2R,3S)-3-{[(7-ethyl-1- A3 C51 637.5 3.12methyl-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-9-yl)carbonyl]amino}-4-(3-fluorophenyl)-2- hydroxybutyl]methylcarbamate(D21) Phenylmethyl ((2R,3S)-3-{[(7-ethyl-1- A3 C52methyl-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-9- yl)carbonyl]amino}-2-hydroxy-4-phenylbutyl)methylcarbamate (D22) Phenylmethyl[(2R,3S)-2-hydroxy-3-({[1- A9 C52methyl-7-(1-methylethyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indol-9-yl]carbonyl}amino)-4-phenylbutyl]methylcarbamate (D23) Phenylmethyl ((2R,3S)-3-{[(7-ethyl-1-A3 C53 methyl-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-9- yl)carbonyl]amino}-2-hydroxy-4-phenylbutyl)carbamate (D24) Phenylmethyl ((2R,3S)-3-{[(6-ethyl-1-  A16C52 methyl-2,2-dioxido-1H- [1,2,5]thiadiazino[3,4,5-hi]indol-8-yl)carbonyl]amino}-2-hydroxy-4- phenylbutyl)methylcarbamate (D25)Description 26

Methyl 7-{[(chloromethyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate(D26)

To a solution of methyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D10)(471 mg, 2.16 mmol, 1 equiv) in CH₂Cl₂ (10 ml) at room temperature wereadded pyridine (260 μl, 3.24 mmol, 1.5 equiv), DMAP (26 mg, 0.22 mmol,0.1 equiv) and chloromethanesulfonyl chloride (354 mg, 2.4 mmol, 1.1equiv) and the resulting mixture was stirred for 2 hours thenpartitioned between AcOEt and a saturated NaHCO₃ aqueous solution. Thetwo layers were separated and the organic phase was washed with H₂O,dried over MgSO₄ and concentrated in vacuo. Trituration of the residuewith Et₂O gave methyl7-{[(chloromethyl)sulfony]amino}-3-ethyl-1H-indole-5-carboxylate (D26)(630 mg, 92%) as a purple solid which was used in the next step withoutfurther purification.

Descriptions 27-29 (D27-D29)

Descriptions 27-29 were obtained from(2S)-2-(1-methylethyl)-3,6-bis(methyloxy)-2,5-dihydropyrazine accordingto the general procedure described in: P. dalla Croce, C. la Rosa, E.Pizzatti Tetrahedron: Asymmetry 2000, 11, 2635-2642: Name Methyl3,5-difluoro-L-phenylalaninate (D27) Methyl 3-fluoro-L-phenylalaninate(D28) Methyl 3-chloro-L-phenylalaninate (D29)Description 30

Ethyl 2-(3-methoxyphenyl)-2-methylpropanoate (D30)

To a solution of ethyl (3-methoxyphenyl)acetate (19.72 g, 0.101 m, 1equiv) in THF (200 ml) was added NaH (8.8 g, 0.222 mol, 2.2 equiv) theniodomethane (26 ml, 0.4 mol, 4 equiv). The resulting mixture was stirredat room temperature for 16 h then partitioned between AcOEt and asaturated NaHCO₃ aqueous solution. The two layers were separated and theorganic phase washed with brine, dried over MgSO₄ and concentrated invacuo to give ethyl 2-(3-methoxyphenyl)-2-methylpropanoate (D30) (20.85g, 98%) as an orange oil which was used in the next step without furtherpurification.

Description 31

Ethyl 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate (D31)

Ethyl 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate (D31) wasobtained from ethyl [3-(trifluoromethyl)phenyl]acetate in an analogousmanner to the process described for Description 30 (D30).

Description 32

2-(3-Methoxyphenyl)-2-methylpropanoic acid (D32)

To a solution of ethyl 2-(3-methoxyphenyl)-2-methylpropanoate (D30)(20.95 g, 94 mmol, 1 equiv) in EtOH (200 ml) was added 2N NaOH aqueoussolution (90 ml, 180 mmol, 1.9 equiv) and the resulting mixture wasstirred at 70° C. for 16 h then cooled to room temperature. Most of EtOHwas removed in vacuo and the residue extracted with AcOEt then acidifiedto pH 1. The aqueous phase was then extracted with AcOEt and the organicphase dried over MgSO₄ and concentrated in vacuo to give2-(3-methoxyphenyl)-2-methylpropanoic acid (D32) (15 g, 82%) as a yellowoil which was used in the next step without further purification.

Description 33

2-Methyl-2-[3-(trifluoromethyl)phenyl]propanoic acid (D33)

2-Methyl-2-[3-(trifluoromethyl)phenyl]propanoic acid (D33) was obtainedfrom ethyl 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoate (D31) in ananalogous manner to the process described for Description 32 (D32).

Description 34

Benzyl [1-(3-methoxyphenyl)-1-methylethyl]carbamate (D34)

To a solution of 2-(3-methoxyhenyl)-2-methylpropanoic acid (D32) (1 g,5.15 mmol, 1 equiv) in toluene (20 ml) at room temperature was addedNEt₃ (1.07 ml, 7.72 mmol, 1.5 equiv) and then diphenylphosphoryl azide(2.2 ml, 10.3 mmol, 2 equiv). The resulting mixture was then heated at80° C. for 2 h then benzyl alcohol (1.61 ml, 15.45 mmol, 3 equiv) wasadded and the solution heated for a further 2 h, cooled to roomtemperature and partitioned between EtOAc and a saturated NaHCO₃ aqueoussolution. The two layers were separated and the aqueous phase dried overMgSO₄ and concentrated in vacuo. Purification of the residue by flashchromatography on silica gel (iso-hexane/AcOEt: 9/1) gave benzyl[1-(3-methoxyphenyl)-1-methylethyl]carbamate (D34) (1 g, 65%) as ayellow gum.

Description 35

Benzyl {1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (D35)

Benzyl {1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (D35) wasobtained from 2-methyl-2-[3-(trifluoromethyl)phenyl]propanoic acid (D33)in an analogous manner to the process described for Description 34(D34).

Description 36

5-Bromo-3-thiophenecarbaldehyde (D36)

To a suspension of 3-thiophenecarbaldehyde (10.6 g, 94.6 mmol, 1 equiv)in CH₂Cl₂ (225 ml) at 0° C. were added AlCl₃ (26.5 g, 199 mmol, 2.1equiv) and Br₂ (5.1 ml, 99 mmol, 1.05 equiv) and the resulting mixturewas refluxed for 7 h then cooled to room temperature. Most of thesolvent was removed in vacuo and the residue was poured slowly onto ice.The aqueous phase was extracted twice with AcOEt and the combinedorganic phases were washed four times with a 2N aqueous HCl solutionthen with a 10% aqueous NaHSO₃ aqueous solution, a saturated NaHCO₃aqueous solution, dried over MgSO₄ and concentrated in vacuo. Theresidue was redissolved in AcOEt and vigorously stirred with a saturatedsolution of Rochelle's salts for 2 h. The layers were separated and theorganic phase dried over MgSO₄ and concentrated in vacuo to give5-bromo-3-thiophenecarbaldehyde (D36) as a brown oil which was used inthe next step without further purification. RT=2.38 min.

Description 37

5-Ethenyl-3-thiophenecarbaldehyde (D37)

To a solution of 5-bromo-3-thiophenecarbaldehyde (D36) (2 g, 10.4 mmol,1 equiv) in DME (45 ml) and H₂O (15 ml) was addedtetrakis(triphenylphosphine)-palladium(0) (600 mg, 0.52 mmol, 0.05equiv), and the suspension was stirred for 10 min.Triethenylboroxin-pyridine complex (prepared according to F. Kerins andD. F. O'Shea in J. Org. Chem, 2002, 67, 4968-4971; 2.64 g, 11 mmol, 1.05equiv) and K₂CO₃ (1.45 g, 10.5 mmol, 1 equiv) were added and theresulting mixture was stirred at 90° C. for 4 h, cooled to roomtemperature and diluted with AcOEt. The organic phase was washed with asaturated NaHCO₃ aqueous solution , dried over MgSO₄ and concentrated invacuo. Purification by flash chromatography on silica gel(iso-hexane/AcOEt: 9/1) gave 5-ethenyl-3-thiophenecarbaldehyde (D37)(660 mg, 100%) of adduct as a pale yellow oil. RT=2.38 min.

Description 38

1,1-Dimethylethyl 2-propyn-1-ylcarbamate (D38)

To a solution of 2-propyn-1-amine (2 g, 36.36 mmol, 1 equiv) in CH₂Cl₂(20 ml) at room temperature were added NEt₃ (5.3 ml, 38.18 mmol, 1.05equiv) and bis(1,1-dimethylethyl)dicarbonate (8.32 g, 38.18 mmol, 1.05equiv) and the resulting mixture was stirred at room temperature for 3 hthen washed with a 2N aqueous HCl solution and a saturated NaHCO₃aqueous solution, dried over MgSO₄ and concentrated in vacuo to give1,1-dimethylethyl 2-propyn-1-ylcarbamate (D38) (4.05 g, 72%) ascolourless needles which were used in the next step without furtherpurification.

Description 39

(1E/Z)-Propanal oxime (D39)

To a solution of hydroxylamine hydrochloride (5 g, 86.2 mmol, 1 equiv)in H₂O (60 ml) were added K₂CO₃ (12.49 g, 90.5 mmol, 1.05 equiv) andpropanal (12.49 g, 90.5 mmol, 1.05 equiv) and the resulting mixture wasstirred at room temperature for 16 h then extracted 3 times with Et₂O.The combined organic phases were dried over MgSO₄ and concentrated invacuo to give (1E/Z)-propanal oxime (D39) (4.59 g, 73%) as a clear oilwhich was used in the next step without further purification.

Description 40

1,1-Dimethylethyl [(3-ethyl-5-isoxazolyl)methyl]carbamate (D40)

To a solution of (1E/Z)-propanal oxime (D39) (4 g, 54.8 mmol, 1 equiv)in CH₂Cl₂ (200 ml) was added N-chloro succinimide (7.44 g, 55.8 mmol,1.02 equiv) and the resulting solution was stirred at room temperaturefor 2.5 h then pyridine (20 ml, excess) was added and the brown solutionstirred for 2 h. 1,1-Dimethylethyl 2-propyn-1-ylcarbamate (D38) (1.36 g,8.72 mmol, 0.16 equiv) and DIPEA (9.5 ml, 55.8 mmol, 1.02 equiv) wereadded and the resulting solution was stirred at room temperature for 48h then washed with a 2N aqueous HCl solution and a saturated NaHCO₃aqueous solution, dried over MgSO₄ and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOEt: 9/1) gave 1,1-dimethylethyl[(3-ethyl-5-isoxazolyl)methyl]carbamate (D40) (1.91 g, 91%) as a clearoil.

Description 41

N-{3-(Dimethylamino)-2-[(dimethyliminio)methyl]-2-propen-1-ylidene}-N-methylmethanaminiumdi-tetrafluoro borate salt (D41)

To 100 ml of DMF (1.34 mol, 15 equiv) at 0° C. was added POCl₃ (25.2 ml,294 mmol, 3.3 equiv) over 2.5 h whilst maintaining the temperature below4° C. To the resulting pale yellow solution was added bromoacetic acid(12.5 g, 89.9 mmol, 1 equiv) and the mixture is stirred at 90° C. for 5h then cooled to room temperature and concentrated in vacuo. To theresidue was cautiously added 2.5 g of ice at 0° C. followed by sodiumtetrafluoroborate (20 g, 182 mmol, 2.0 equiv) in H₂O (40 ml). Thesolution was cooled to −30° C. and the precipitate formed was filteredoff and triturated with CH₃CN to giveN-{3-(dimethylamino)-2-[(dimethyliminio)methyl]-2-propen-1-ylidene}-N-methylmethanaminiumdi-tetrafluoro borate salt (D41) (11.8 g, 33 mmol, 37%) as a white solidwhich was used in the next step without further purification.

Description 42

(Hydroxymethylidene)propanedial (D42)

To a solution ofN-{3-(dimethylamino)-2-[(dimethyliminio)methyl]-2-propen-1-ylidene}-N-methylmethanaminiumdi-tetrafluoro borate salt (D41) (11.8 g, 33 mmol, 1 equiv) in H₂O (36ml) was added K₂CO₃ (1.8 g, 13 mmol, 0.4 equiv) and the resultingmixture was stirred at 40° C. for 5 min. then cooled to room temperatureand concentrated HCl (29 ml) was slowly added. The aqueous phase wasextracted 5 times with CH₂Cl₂ and the combined organic phases were driedover MgSO₄ and concentrated in vacuo to give(hydroxymethylidene)propanedial (D42) (2.25 g, 68%) as a white solidwhich was used immediately.

Description 43

1-(2,2,2-Trifluoroethyl)-1H-pyrazole-4-carbaldehyde (D43)

To a solution of (hydroxymethylidene)propanedial (D42) (2.25 g, 22.5mmol, 1 equiv) in MeOH (300 ml) and concentrated HCl (4.4 ml) at roomtemperature was added (2,2,2-trifluoroethyl)hydrazine hydrochloride(3.39 g, 150 mmol, 6.7 equiv) and the resulting mixture was stirred for16 h at room temperature then concentrated in vacuo. The residue waspartitioned between AcOEt and H₂O and the two layers were separated. Theaqueous phase was dried over MgSO₄ and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOEt: 4/1 to 1/1) gave1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbaldehyde (D43) (2.8 g, 83%)as a pale yellow oil.

Description 44

1,1-Dimethylethyl[(1S)-2-(cyclohexylamino)-1-methyl-2-oxoethyl]carbamate (D44)

N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (1.5 g, 8.0 mmol, 1equiv), EDAC.HCl (1.84 g, 9.6 mmol, 1.2 equiv), HOBT (1.47 g, 9.6 mmol,1.2 equiv), 4-ethylmorpholine (1.76 g, 16 mmol, 2 equiv) andcyclohexylamine (1.1 ml, 9.6 mmol, 1.2 equiv) in CH₂Cl₂ (10 ml) werestirred at room temperature for 16 h. The solution was concentrated invacuo and the residue dissolved in AcOEt. The organic phase was washedwith 2N aqueous HCl solution, saturated aqueous NaHCO₃ solution andbrine, dried over MgSO₄ and concentrated in vacuo to give1,1-dimethylethyl[(1S)-2-(cyclohexylamino)-1-methyl-2-oxoethyl]carbamate (D44) (2.12 g,98%) as a colourless oil which was used in the next step without furtherpurification.

Description 45

4-((Z/E)-But-2-enylamino)-3,5-diiodo-benzoic acid ethyl ester (D45)

To a solution of 4-amino-3,5-diiodo-benzoic acid ethyl ester(commercially available from Maybridge) (72.6 g, 0.17 mmol, 1 equiv) inDMF (450 ml) at 0° C. under nitrogen was added NaH (60% in mineral oil,7.3 g, 0.18 mmol, 1.05 equiv) portionwise over 2 min. After 10 mincrotyl bromide (21.5 ml, 0.21 mmol, 1.2 equiv) in DMF (50 ml) was addedvia cannula over 5 min and the resulting mixture was allowed to warm toroom temperature over 30 min. 5 ml of EtOH were added and the mixturewas concentrated in vacuo. The residue was dissolved in AcOEt and theorganic phase was washed with H₂O. The aqueous phase was extracted withAcOEt and the combined organic phases were washed with brine, dried overMgSO₄ and concentrated in vacuo to give the title compound (D45) (82 g,100%) as a pink solid which was used in the next step without furtherpurification. [M+H]⁺=472.0, RT=4.93 min.

Description 46

3-Ethyl-7-iodo-1H-indole-5-carboxylic acid ethyl ester (D46)

To a solution of 4-((Z/E)-but-2-enylamino)-3,5-diiodo-benzoic acid ethylester (D45) (15 g, 31.8 mmol, 1 equiv) in DMF (150 ml) at roomtemperature under nitrogen were added Pd(OAc)₂ (357 mg, 1.6 mmol, 0.05equiv), NaCOOH (6.5 g, 95.6 mmol, 3 equiv), Na₂CO₃ (8.4 g, 79.6 mmol,2.5 equiv) and Nbu₄Cl (8.0 g, 35.0 mmol, 1.1 equiv). The resultingsuspension was stirred under nitrogen at 80° C. for 30 min then cooledto room temperature and concentrated in vacuo. The residue waspartitioned between AcOEt and H₂O and the two phases were separated. Theorganic phase was dried over MgSO₄ and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOEt: 9/1) gave the title compound (D46) (6.3 g, 58%) as awhite solid. [M+H]⁺=344.0, RT=3.86 min.

Description 47

7-Benzyloxycarbonylamino-3-ethyl-1H-indole-5-carboxylic acid ethyl ester(D47)

To a solution of 3-ethyl-7-iodo-1H-indole-5-carboxylic acid ethyl ester(D46) (850 mg, 2.48 mmol, 1 equiv) in toluene (20 ml) at roomtemperature under nitrogen were added benzyl carbamate (562 mg, 3.72mmol, 1.5 equiv), copper iodide (24 mg, 0.13 mmol, 0.05 equiv) K₃PO₄(1.05 g, 4.8 mmol, 2 equiv) and N,N′-dimethylethylenediamine (26 μl,0.25 mmol, 0.1 equiv) and the resulting suspension was stirred at 100°C. for 30 min then cooled to room temperature and concentrated in vacuo.The residue was partitioned between AcOEt and H₂O and the two phaseswere separated. The organic phase was dried over MgSO₄ and concentratedin vacuo. Purification of the residue by flash chromatography on silicagel (iso-hexane/AcOEt: 9/1) gave the title compound (D47) (250 mg, 27%)as an off white solid. [M+H]⁺=367.1, RT=3.73 min.

Description 48

7-Amino-3-ethyl-1H-indole-5-carboxylic acid ethyl ester (D48)

To a solution of 7-benzyloxycarbonylamino-3-ethyl-1H-indole-5-carboxylicacid ethyl ester (D47) (250 mg, 0.68 mg, 1 equiv) in EtOH (10 ml) wereadded NH₄COOH (431 mg, 6.8 mmol, 10 equiv), H₂O (2 ml), Pd (10% w/w oncharcoal, 50 mg, 0.02 equiv w/w) and the resulting mixture was stirredat 70° C. for 1.5 h. Another 200 mg of Pd (10% w/w on charcoal, 0.08equiv w/w) were then added and the resulting mixture stirred at 70° C.for another 30 min then cooled to room temperature. The catalyst wasfiltered off through a pad of celite and most of the EtOH was removed invacuo. The residue was partitioned between AcOEt and H₂O and the twophases were separated. The organic phase was dried over MgSO₄ andconcentrated in vacuo to give the title compound (D48) (150 mg, 95%) asan off white solid which was used in the next step without furtherpurification. [M+H]⁺=233.1, RT=3.19 min.

Description 49

7-(3-Chloro-propanoylamino)-3-ethyl-1H-indole-5-carboxylic acid ethylester (D49)

To a solution of 7-amino-3-ethyl-1H-indole-5-carboxylic acid ethyl ester(D48) (300 mg, 1.29 mmol, 1 equiv) in CH₂Cl₂ (10 ml) were added NEt₃(216 μl, 1.55 mmol, 1.2 equiv) and 3-chloropropionyl chloride (136 μl,1.42 mmol, 1.1 equiv) and the resulting solution was stirred at roomtemperature for 48 h then diluted with AcOEt and washed with H₂O. Theorganic phase was dried over MgSO₄ and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOEt: 3/1) gave the title compound (D49) (300 mg, 72%) as awhite solid. [M+H]⁺=323.4, RT=3.18 min.

Description 50

7-Ethenesulfonylamino-3-ethyl-1H-indole-5-carboxylic acid ethyl ester(D50)

To a solution of 7-amino-3-ethyl-1H-indole-5-carboxylic acid ethyl ester(D48) (1.1 g, 4.74 mmol, 1 equiv) in CH₂Cl₂ (20 ml) at room temperaturewere added pyridine (575 μl, 7.11 mmol, 1.5 equiv), DMAP (66 mg, 0.47mmol, 0.1 equiv) and 2-chloroethanesulfonyl chloride (545 μl, 5.22 mmol,1.1 equiv) and the resulting mixture was stirred for 5 min then dilutedwith AcOEt. The organic phase was washed with a 2N aqueous HCl solution,dried over MgSO₄ and concentrated in vacuo. The residue was dissolved inCH₂Cl₂ (20 ml) and NEt₃ (1 ml, excess) was added and the resultingsolution was stirred at room temperature for 16 h then diluted withAcOEt. The organic phase was washed with H₂O, 2N aqueous HCl solutionand brine, dried over MgSO₄ and concentrated in vacuo to give crudetitle compound (D50) (1.7 g, 110%) as a brown oil which was used in thenext step without further purification. [M+H]⁺=323.1, RT=3.29 min.

Description 51

[(1S,2R)-1-Benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-carbamicacid tert-butyl ester (D51)

((S)—(S)-1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (10g, 38 mmol, 1 equiv) [Chirex 1819W94 Lot#9924382] was dissolved in EtOH(100 ml) and 3-methoxy-benzylamine (14.6 ml, 114 mmol, 3 equiv) wasadded. The resulting mixture was heated, under an atmosphere ofnitrogen, for 12 h at reflux temperature. The mixture was cooled and thesolvent was removed by evaporation in vacuo. The residue was dissolvedin AcOEt and washed three times with H₂O, dried over MgSO₄ andconcentrated in vacuo. Purification by flash chromatography on silicagel (CH₂Cl₂/MeOH: 98/2 to 95/5) gave the title compound (D51) (10.0 g,66%) as a white solid.

Description 52

1,1-Dimethylethyl (4,4-difluorocyclohexyl)carbamate (D52)

To a solution of 1,1-dimethylethyl (4-oxocyclohexyl)carbamate (3.56 g,16.7 mmol, 1 equiv) in CH₂Cl₂ (50 ml) was added DAST (4.6 ml, 35.1 mmol,2.1 equiv) and the resulting mixture was stirred at room temperature for16 h. A saturated aqueous NaHCO₃ solution (20 ml) was added and thebiphasic mixture was vigorously stirred at room temperature for 1 h. Thelayers were separated and the aqueous phase extracted with CH₂Cl₂. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.Trituration of the residue with hexane gave 1,1-dimethylethyl(4,4-difluorocyclohexyl)carbamate (D52) (1.7 g, 43%) as a white solidwhich was used in the next step without further purification.

Description F1

[1-(3-Methoxyphenyl)-1-methylethyl]amine (F1)

A flask was charged with benzyl[1-(3-methoxyphenyl)-1-methylethyl]carbamate (D34) (1 g, 3.34 mmol, 1equiv), 10% palladium on charcoal (50% wet, 100 mg, 10% w/w), NH₄COOH(2.1 g, 33 mmol, 10 equiv), EtOH (40 ml) and H₂O (8 ml). The resultingmixture was stirred at 80° C. for 2 h, cooled to room temperature andthe catalyst was filtered off using a pad of celite. Most of the EtOHwas removed in vacuo and the residue was diluted with 1N HCl aqueoussolution. The aqueous phase was extracted with AcOEt then basified to pH13 and extracted twice with AcOEt. These combined organic layers weredried over MgSO₄ and concentrated in vacuo to[1-(3-methoxyphenyl)-1-methylethyl]amine (F1) (290 mg, 53%) as a yellowgum which was used in the next step without further purification.

Description F2

2-[3-(Trifluoromethyl)phenyl]propan-2-amine (F2)

2-[3-(Trifluoromethyl)phenyl]propan-2-amine (F2) was obtained frombenzyl (1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (D35) inan analogous manner to the process described for Description F1 (F1).

Description F3

2,6-Dimethyl-2-heptanamine (F3)

2,6-Dimethyl-2-heptanamine (F3) was obtained according to S. S. Berg andD. T. Cowling, J. Chem. Soc. (C) 1971, 1653-1658.

Description F4

[(3-Ethyl-5-isoxazolyl)methyl]amine hydrochloride (F4)

1,1-Dimethylethyl [(3-ethyl-5-isoxazolyl)methyl]carbamate (D40) (1.28 g,5.53 mmol, 1 equiv) was dissolved in a 4M HCl solution in dioxan (20 ml)and the resulting solution was stirred at room temperature for 2 h thenconcentrated in vacuo. Trituration of the residue with Et₂O gave[(3-ethyl-5-isoxazolyl)methyl]amine hydrochloride (F4) (0.82 g, 92%) asa white solid which was used in the next step without furtherpurification.

Description F5

N¹-Cyclohexyl-L-alaninamide hydrochloride salt (F5)

N¹-Cyclohexyl-L-alaninamide hydrochloride salt (F5) was obtained from1,1-dimethylethyl[(1S)-2-(cyclohexylamino)-1-methyl-2-oxoethyl]carbamate (D44) in ananalogous manner than for Description F4.

Description F6

4,4-Difluorocyclohexanamine tosic salt (F6)

1,1-Dimethylethyl (4,4-difluorocyclohexyl)carbamate (D52) (1.0 g, 4.25mmol, 1 equiv) was dissolved in CH₃CN (20 ml) and PTSA.H₂O (1.61 g, 8.5mmol, 2 equiv) was added. The resulting mixture was stirred for 16 h.The precipitate formed was filtered off and triturated with Et₂O to give4,4-difluorocyclohexanamine tosic salt (F6) (865 mg, 66%) as a whitesolid which was used in the step without further purification.

Preparation of Epoxides

Epoxide 1

1,1-Dimethylethyl{(1S)-2-(3,5-difluorophenyl)-1-[(2S)-2-oxiranyl]ethyl}carbamate (K1)

1,1-Dimethylethyl{(1S)-2-(3,5difluorophenyl)-1-[(2S)-2-oxiranyl]ethyl}carbamate (K1) wasobtained from methyl 3,5-difluoro-L-phenylalaninate (D27) according tothe procedure described in Patent US 2003/0004360 A1.

Epoxides 2-3 (K2-K3)

Epoxides 2-3 were obtained in an analogous manner to the processdescribed for Epoxide 1 (K1) using the appropriate alaninate indicatedin the table below: Name Precursor 1,1-Dimethylethyl{(1S)-2-(3-fluorophenyl)-1-[(2S)-2- D28 oxiranyl]ethyl}carbamate (K2)1,1-Dimethylethyl {(1S)-2-(3-chlorophenyl)-1-[(2S)-2- D29oxiranyl]ethyl}carbamate (K3)Preparation of EstersEster 1

Methyl7-ethyl-2-oxo-1,2,3,4-tetrahydro[1,4]diazepino[3,2,1-hi]indole-9-carboxylate(B1)

To a solution of methyl7-[(3-chloropropanoyl)amino]-3-ethyl-1H-indole-5-carboxylate (D16) (300mg, 0.93 mmol, 1 equiv) in DMF (10 ml) at room temperature undernitrogen was added NaH (60% in mineral oil, 41 mg, 1.02 mmol, 1.1equiv). The resulting solution was heated to 100° C. for 1 h and thencooled to room temperature. Excess NaH was neutralised with MeOH (2 ml)and the solution was concentrated in vacuo. The residue was dissolved inAcOEt and the organic phase was washed with H₂O, dried over MgSO₄ andconcentrated in vacuo. Purification of the residue by flashchromatography on silica gel (iso-hexane/AcOEt: 2/3) gave methyl7-ethyl-2-oxo-1,2,3,4-tetrahydro[1,4]diazepino[3,2,1-hi]indole-9-carboxylate(B1) (120 mg, 45%) as a white solid. [M+H]⁺=273.0, RT=3.08 min.

Ester 2

Methyl7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B2)

To a solution of methyl7-[(ethenylsulfonyl)amino]-3-ethyl-1H-indole-5-carboxylate (D13) (2.98g, 9.69 mmol, 1 equiv) in DMF (40 ml) at room temperature under nitrogenwas added NaH (60% in mineral oil, 465 mg, 11.6 mmol, 1.2 equiv). After5 min, the mixture was heated to 100° C. for 1 h and then cooled to roomtemperature. MeOH (1 ml) was added and the solution was concentrated invacuo. The residue was dissolved in AcOEt and the organic phase waswashed with a saturated NaHCO₃ aqueous solution, dried over MgSO₄ andconcentrated in vacuo. Trituration of the residue with Et₂O gave methyl7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B2) (1.67 g, 55%) as a brown solid which was used in thenext step without further purification. [M+H]⁺=309.3, RT=2.93 min.

Ester 3 (Procedure A)

Methyl7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B3)

To a solution of methyl7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B2) (2.07 g, 6.74 mmol, 1 equiv) in DMF (50 ml) at roomtemperature under nitrogen were added K₂CO₃ (4.65 g, 33.7 mmol, 5 equiv)and iodomethane (2.1 ml, 33.7 mmol, 5 equiv). The resulting mixture wasstirred at 80° C. for 1 h then cooled to room temperature, filteredthrough a pad of celite and concentrated in vacuo. The residue wasdissolved in AcOEt and the organic phase was washed with a saturatedNaHCO₃ aqueous solution, dried over MgSO₄ and concentrated in vacuo.Trituration of the residue with Et₂O gave methyl7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B3) (1.58 g, 73%) as a white solid which was used in thenext step without further purification. [M+H]⁺=323.1, RT=2.90 min.

Ester 3 (Procedure B)

Methyl7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B3)

To a solution of methyl7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B2) (191 mg, 0.62 mmol, 1 equiv) in DMF (3 ml) at roomtemperature were added NaH (60% dispersion in mineral oil, 50 mg, 1.25mmol, 2 equiv) and iodomethane (46 μl, 0.74 mmol, 1.2 equiv) and theresulting solution was stirred for 1 h then partitioned between AcOEtand a saturated NaHCO₃ aqueous solution. The two layers were separatedand the organic phase was washed with brine, dried over MgSO₄ andconcentrated in vacuo. Purification of the residue by flashchromatography on silica gel (iso-hexane/AcOEt: 4/1 to 1/1) gave methyl7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B3) (44 mg, 22%) as a brown gum.

Ester 4

Methyl7-ethyl-1-phenyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B4)

To a solution of methyl7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B2) (200 mg, 0.65 mmol, 1 equiv) in CH₂Cl₂ (30 ml) wereadded phenylboronic acid (312 mg, 2.5 mmol, 3.8 equiv), Cu(OAc)₂ (228mg, 1.25 mmol, 1.9 equiv), NEt₃ (350 μl, 2.5 mmol, 3.8 equiv) andpowered activated 4A molecular sieves (300 mg, 150% w/w). The resultingmixture was stirred at room temperature for 2 h then the molecularsieves were filtered off through a pad of celite and the organic phasewas washed with 2N HCl aqueous solution and a 2N NaOH aqueous solution,dried over MgSO₄ and concentrated in vacuo. Purification of the residueby flash chromatography on silica gel (iso-hexane/AcOEt: 1/2) gavemethyl7-ethyl-1-phenyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B4) (30 mg, 12%) as a white solid. [M+H]⁺=385.2, R.T.=3.54min.

Ester 5

Methyl7-ethyl-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B5)

Methyl7-ethyl-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylate2,2-dioxide (B5) was obtained as a by-product of the synthesis of Ester3 (Procedure B).

Esters 9 and 11 (B9 and B11)

Esters 9 and 11 (B9 and B11) were obtained in an analogous manner tothat described for Ester 3 (Procedure A) using the appropriate precursorindicated in the table below: RT Name Precursor [M + H]⁺ (min.) Methyl1-methyl-7-(1-methylethyl)-3,4- D18 337.4 3.13dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxylate2,2-dioxide (B9) Methyl 1-methyl-7-propyl-3,4-dihydro- D17 337.2 3.131H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxylate 2,2-dioxide (B11)Esters B6-B8, B10 and B12-B13

The following esters were obtained using an analogous manner to thatdescribed for Ester 3 (Procedure A) from the appropriate precursor andalkylating reagent indicated in the table below: Alkylating RT NamePrecursor Reagent [M + H]⁺ (min.) Methyl 6-ethyl-1-(phenylmethyl)-9a,9b-dihydro-1H-[1,2,5]thiadiazino[3,4,5- hi]indole-8-carboxylate 2,2-dioxide(B6) B2

— — Methyl 7-ethyl-1-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxylate2,2-dioxide (B7) B2

351.4 3.40 Methyl 1,7-diethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9- carboxylate 2,2-dioxide (B8) B2

337.5 3.30 Methyl 7-ethyl-1-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxylate2,2-dioxide (B10) B2

391.4 3.36 Methyl 1-ethyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9- carboxylate 2,2-dioxide (B12)D17

351.2 3.26 Methyl 1-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}-7-ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9- carboxylate 2,2-dioxide (B13) B2

440.4 ([M +NH₃ + H]⁺) 3.46Ester 14

Methyl 6-ethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B14)

To a solution of methyl7-{[(chloromethyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate (D26)(630 mg, 1.91 mmol, 1 equiv) in DMF (10 ml) at room temperature wasadded NaH (60% dispersion in mineral oil, 153 mg, 3.82 mmol, 2 equiv)and after 5 min the solution was stirred at 100° C. for 1 hour thencooled to room temperature. NaH (60% dispersion in mineral oil, 50 mg,1.25 mmol, 0.6 equiv) was added and the solution stirred at 100° C. foranother 1 h then cooled to room temperature and concentrated in vacuo.The residue was partitioned between AcOEt and a 2N aqueous HCl solution.The two layers were separated and the organic phase was washed with asaturated NaHCO₃ aqueous solution and brine, dried over MgSO₄ andconcentrated in vacuo. Purification of the residue by flashchromatography on silica gel (iso-hexane/AcOEt: 9/1 to 1/1) gave methyl6-ethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate 2,2-dioxide(B14) (143 mg, 41%) as a brown solid.

Ester 16

Methyl6-ethyl-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B16)

To a solution of methyl6-ethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate 2,2-dioxide(B14) (27 mg, 91 μmol, 1 equiv) in DMF (1 ml) at room temperature wereadded NaH (60% dispersion in mineral oil, 7 mg, 0.182 mmol, 2 equiv) andiodomethane (200 μl, 3.2 mmol, excess) and the resulting solution wasstirred for 1 h then partitioned between AcOEt and a suturated NaHCO₃aqueous solution. The two layers were separated and the organic phasewas washed with brine, dried over MgSO₄ and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOEt: 9/1 to 4/1) gave methyl6-ethyl-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B16) (20 mg, 71%) as a brown solid. [M+H]⁺=309.1, R.T.=2.90min.

Ester 15

Methyl6-ethyl-1,3-dimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B15)

Methyl6-ethyl-1,3-dimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B15) was obtained as a by-product of the synthesis of esterB16.

Ester 17

Methyl6-ethyl-1,3,3-trimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B17)

Methyl6-ethyl-1,3,3-trimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxylate2,2-dioxide (B17) was obtained as a by-product of the synthesis of esterB16.

Ester 18

7-Ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid ethyl ester (B18)

To a solution of7-(3-chloro-propanoylamino)-3-ethyl-1H-indole-5-carboxylic acid ethylester (D49) (300 mg, 0.93 mmol, 1 equiv) in DMF (10 ml) at roomtemperature under nitrogen was added NaH (60% in mineral oil, 41 mg,1.02 mmol, 1.1 equiv). The resulting solution was heated to 100° C. for1 h and then cooled to room temperature. Excess NaH was neutralised withEtOH (2 ml) and the solution was concentrated in vacuo. The residue wasdissolved in AcOEt and the organic phase was washed with H₂O, dried overMgSO₄ and concentrated in vacuo. Purification of the residue by flashchromatography on silica gel (iso-hexane/AcOEt: 2/3) gave the titlecompound (B18) (120 mg, 45%) as a white solid. [M+H]⁺=287.0, RT=3.08min.

Ester 19

2-Ethyl-7,7-dioxo-6,7,8,9-tetrahydro-7l⁶-thia-6,9a-diaza-benzo[cd]azulene-4-carboxylicacid ethyl ester (B19)

To a solution of 7-ethenesulfonylamino-3-ethyl-1H-indole-5-carboxylicacid ethyl ester (D50) (130 mg, 0.4 mmol, 1 equiv) in DMF (10 ml) atroom temperature under nitrogen was added NaH (60% in mineral oil, 19mg, 0.45 mmol, 1.2 equiv). After 5 min, the mixture was heated to 100°C. for 1 h and then cooled to room temperature. EtOH (1 ml) was addedand the solution was diluted with AcOEt. The organic phase was washedwith 2N aqueous HCl solution, dried over MgSO₄ and concentrated in vacuoto give the title compound (B19) (100 mg, 77%) as a brown solid whichwas used in the next step without further purification. [M+H]⁺=323.3,RT=2.93 min.

Ester 20

2-Ethyl-6-methyl-7,7-dioxo-6,7,8,9-tetrahydro-7l⁶-thia-6,9a-diaza-benzo[cd]azulene-4-carboxylicacid ethyl ester (B20)

To a solution of2-ethyl-7,7-dioxo-6,7,8,9-tetrahydro-7l⁶-thia-6,9a-diaza-benzo[cd]azulene-4-carboxylicacid ethyl ester (B19) (200 mg, 0.621 mmol, 1 equiv) in DMF (10 ml) atroom temperature under nitrogen were added NaH (60% in mineral oil, 50mg, 1.24 mmol, 2 equiv) and, after 2 min, Mel (46 μl, 0.74 mmol, 1.2equiv). The resulting mixture was stirred at room temperature for 30 minthen EtOH (1 ml) was added and the solution concentrated in vacuo. Theresidue was dissolved in AcOEt and the organic phase was washed withH₂O, dried over MgSO₄ and concentrated in vacuo. Purification of theresidue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1)gave the title compound (B20) (150 mg, 76%) as a white solid.[M+H]⁺=337.1, RT=3.24 min.

Ester 21

2-Ethyl-7,7-dioxo-6-phenyl-6,7,8,9-tetrahydro-7l⁶-thia-6,9a-diaza-benzo[cd]azulene-4-carboxylicacid ethyl ester (B21)

To a solution of2-ethyl-7,7-dioxo-6,7,8,9-tetrahydro-7l⁶-thia-6,9a-diaza-benzo[cd]azulene-4-carboxylicacid ethyl ester (B19) (200 mg, 0.62 mmol, 1 equiv) in CH₂Cl₂ (30 ml)were added phenylboronic acid (312 mg, 2.5 mmol, 4 equiv), copper (II)acetate (220 mg, 1.25 mmol, 2 equiv), NEt₃ (350 ml, 2.5 mmol, 4 equiv)and activated 4 A molecular sieves (300 mg). The resulting mixture wasstirred at room temperature for 2 h and then filtered. The filtrate waswashed with 2N aqueous HCl solution, a 2N aqueous NaOH solution, driedover MgSO₄ and concentrated in vacuo. Purification of the residue byflash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave thetitle compound (B21) (30 mg, 12%) as a white solid. [M+H]⁺=399.2,RT=3.54 min.

Preparation of BOC-Protected Amines

BOC-Protected Amine 1

Tert-butyl[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]carbamate (H1)

Tert-butyl {(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethyl}carbamate (10 g, 38mmol, 1 equiv) [Chirex 1819W94 Lot#9924382] was dissolved in EtOH (100ml) and cyclohexylamine (13 ml, 114 mmol, 3 equiv) was added. Theresulting mixture was heated, under an atmosphere of nitrogen, for 12 hat reflux temperature. The mixture was cooled and the solvent wasremoved by evaporation in vacuo. The resulting white solid was washedwith H₂O and then with Et₂O before drying in vacuo to give tert-butyl[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]carbamate (H1)(9.0 g, 66%). [M+H]⁺=363.2

BOC-Protected Amines 2-46 (H2-H46)

BOC-protected amines 2-46 were prepared in an analogous manner to thatdescribed for BOC-protected amine H1, substituting cyclohexylamine withthe appropriate epoxide or amine indicated in the table below (if notcommercially available): Epoxide Amine BOC-protected amine precursorprecursor Tert-butyl {(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino] propyl}carbamate (H2) Tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-{[3- (trifluoromethyl)benzyl]amino}propyl)carbamate (H3) Tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-{[1-(3- F1methoxyphenyl)-1-methylethyl]amino}propyl)carbamate (H4) Tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3-({1-methyl-1- F2[3-(trifluoromethyl)phenyl] ethyl}amino)propyl] carbamate (H5)Tert-butyl ((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)carbamate (H6) Tert-butyl[(1S,2R)-1-benzyl-3-(benzylamino)-2- hydroxypropyl]carbamate (H7)Tert-butyl {(1S,2R)-1-benzyl-2-hydroxy-3-[(2- methylbenzyl)amino]propyl}carbamate (H8) Tert-butyl {(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino] propyl}carbamate (H9) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(4- methylbenzyl)amino] propyl}carbamate(H10) Tert-butyl {(1S,2R)-1-benzyl-2-hydroxy-3-[(pyridin-2-ylmethyl)amino]propyl} carbamate (H11) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(pyridin-3- ylmethyl)amino]propyl}carbamate (H12) Tert-butyl {(1S,2R)-1-benzyl-2-hydroxy-3-[(pyridin-4-ylmethyl)amino]propyl} carbamate (H13) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(2- phenylethyl)amino] propyl}carbamate(H14) Tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl] carbamate (H15) Tert-butyl{(1S,2R)-1-benzyl-3-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}carbamate (H16) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(1,1,5- F3 trimethylhexyl)amino]propyl}carbamate (H17) Tert-butyl((1S,2R)-1-benzyl-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)carbamate (H18) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(2- methoxyethyl)amino] propyl}carbamate(H19) Tert-butyl [(1S,2R)-1-benzyl-3-(ethylamino)-2-hydroxypropyl]carbamate (H20) Tert-butyl{(1S,2R)-1-benzyl-3-[(2-fluoroethyl)amino]-2- hydroxypropyl}carbamate(H21) Tert-butyl {(1S,2R)-1-benzyl-3-[(2,2-difluoroethyl)amino]-2-hydroxypropyl}carbamate (H22) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(2,2,2- trifluoroethyl)amino]propyl}carbamate (H23) Tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-(propylamino)propyl] carbamate (H24) Tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3- (isopropylamino)propyl] carbamate (H25)Tert-butyl [(1S,2R)-1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl]carbamate (H26) Tert-butyl{(1S,2R)-1-benzyl-2-hydroxy-3-[(2,2,3,3,3-pentafluoropropyl)amino]propyl}carbamate (H27) Tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3-(prop-2-yn-1- ylamino)propyl] carbamate(H28) Tert-butyl [(1S,2R)-1-benzyl-3-(butylamino)-2-hydroxypropyl]carbamate (H29) Tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1- methylpropyl]amino}propyl)carbamate (H30) Tert-butyl((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1- methylpropyl]amino}propyl)carbamate (H31) Tert-butyl{(1S,2R)-1-benzyl-3-[(cyclopropylmethyl)amino]-2-hydroxypropyl}carbamate (H32) Tert-butyl[(1S,2R)-1-benzyl-2-hydroxy-3- (isobutylamino)propyl] carbamate (H33)Tert-butyl [(1S,2R)-1-benzyl-3-(cyclobutylamino)-2-hydroxypropyl]carbamate (H34) Tert-butyl[(1S,2R)-1-benzyl-3-(Tert-butylamino)-2- hydroxypropyl]carbamate (H35)Tert-butyl [(1S,2R)-1-benzyl-3-(cyclopentylamino)-2-hydroxypropyl]carbamate (H36) 1,1-Dimethylethyl[(1S,2R)-3-[(2,2-dimethyltetrahydro- 2H-pyran-4-yl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamate (H37) 1,1-Dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]- K33-(cyclopropylamino)-2-hydroxypropyl]carbamate (H38) 1,1-Dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]- K33-(cyclohexylamino)-2-hydroxypropyl]carbamate (H39) 1,1-Dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]- K32-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl] carbamate (H40)1,1-Dimethylethyl {(1S,2R)-3-(cyclopropylamino)-1-[(3- K2fluorophenyl)methyl]-2-hydroxypropyl}carbamate (H41) 1,1-Dimethylethyl{(1S,2R)-3-(cyclohexylamino)-1-[(3- K2fluorophenyl)methyl]-2-hydroxypropyl}carbamate (H42) 1,1-Dimethylethyl[(1S,2R)-1-[(3-fluorophenyl)methyl]-2- K2hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl] carbamate (H43)1,1-Dimethylethyl {(1S,2R)-3-(cyclopropylamino)-1- K1[(3,5-difluorophenyl)methyl]-2-hydroxypropyl}carbamate (H44)1,1-Dimethylethyl {(1S,2R)-3-(cyclohexylamino)-1-[(3,5- K1difluorophenyl)methyl]-2-hydroxypropyl}carbamate (H45) 1,1-Dimethylethyl[(1S,2R)-1-[(3,5- K1 difluorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl] carbamate (H46)BOC-Protected Amine 47

1,1-Dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]-2-hydroxy-3-(methylamino)propyl]carbamate(H47)

To a solution of methylamine (2N in MeOH, 6 ml, 12 mmol, 7.1 equiv) wasadded 1,1-dimethylethyl{(1S)-2-(3-chlorophenyl)-1-[(2S)-2-oxiranyl]ethyl}carbamate (K3) (500mg, 1.68 mmol, 1 equiv) and the resulting mixture was stirred at 60° C.for 10 min with microwaves activation then cooled to room temperatureand concentrated in vacuo to give 1,1-dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]-2-hydroxy-3-(methylamino)propyl]carbamate(H47) (245 mg, 44%) as a cream coloured solid which was used in the nextstep without further purification. [M+H]⁺=329.4, RT=2.13 min.

BOC-Protected Amines 48-49 (H48-H49)

Boc-protected amines 48-49 were obtained in an analogous manner to theprocedure described for BOC-protected Amine 47 using the appropriateepoxide indicated in the table below: Precursor Boc-protected amineepoxide [M + H]+ RT (min) 1,1-Dimethylethyl [(1S,2R)-1-[(3- K2 313.51.98 fluorophenyl)methyl]-2-hydroxy-3- (methylamino)propyl]carbamate(H48) 1,1-Dimethylethyl [(1S,2R)-2-hydroxy-3- (methylamino)-1-(phenylmethyl)propyl]carbamate (H49)

295.5 1.97BOC-protected Amine 50

Phenylmethyl[(2R,3S)-4-(3-chlorophenyl)-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxybutyl]methylcarbamate(H50)

To a solution of 1,1-dimethylethyl[(1S,2R)-1-[(3-chlorophenyl)methyl]-2-hydroxy-3-(methylamino)propyl]carbamate(H47) (245 mg, 0.75 mmol, 1 equiv)in CH₂Cl₂ (5 ml) at 0° C. were addedpyridine (91 ml, 1.12 mmol, 1.5 equiv) and phenylmethylchloridocarbonate (117 ml, 0.825 mmol, 1.1 equiv) and the resultingsolution was stirred at this temperature for 4 h then concentrated invacuo. Purification of the residue by flash chromatography on silica gel(iso-hexane/AcOet: 4/1 to 1/1) gave phenylmethyl[(2R,3S)-4-(3-chlorophenyl)-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxybutyl]methylcarbamate(H50) (227 mg, 66%) as a white foam. [M+H]⁺=463.4, RT=3.58 min.

BOC-Protected Amines 51-52 (H51-H52)

Boc-protected amines H51-H52 were obtained in an analogous manner to theprocedure described for BOC-protected Amine 50 using the appropriateprecursor indicated in the table below: Boc-protected amine Precursor[M + H]+ RT (min) 1,1-Dimethylethyl [(1S,2R)-1-[(3-fluorophenyl) H48447.4 3.39 methyl]-2-hydroxy-3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl] carbamate (H51) 1,1-Dimethylethyl[(1S,2R)-2-hydroxy-3- H49 — —(methyl{[(phenylmethyl)oxy]carbonyl}amino)-1-(phenylmethyl)propyl]carbamate (H52)BOC-Protected Amine 53

1,1-Dimethylethyl[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[(phenylmethyl)oxy]carbonyl}amino)propyl]carbamate(H53)

A solution of 1,1-dimethylethyl[(1S,2R)-3-amino-2-hydroxy-1-(phenylmethyl)propyl]carbamate (D19) (25.6g, 91.4 mmol, 1 equiv) in DMF (250 ml) at 0° C. was treated with NEt₃(15ml, 108 mmol, 1.2 equiv) and then with benzyl chloroformate (14 ml, 98mmol, 1.1 equiv) in DMF (50 ml) dropwise. The resulting solution wasstirred at 0° C. for 1 h and at room temperature for 16 h and thenconcentrated in vacuo. The residue was partitioned between AcOEt andsaturated aqueous NaHCO₃ solution. The resulting precipitate was dilutedwith H₂O and filtered to give 1,1-dimethylethyl[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[(phenylmethyl)oxy]carbonyl}amino)propyl]carbamate(H53) (31.5 g, 83%) as a white solid which was used in the next stepwithout further purification.

BOC-Protected Amine 54

1,1-Dimethylethyl[(1S,2R)-3-{[(6-bromo-2-pyridinyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate(H54)

To a solution of 1,1-dimethylethyl[(1S,2R)-3-amino-2-hydroxy-1-(phenylmethyl)propyl]carbamate (D19) (280mg, 1 mmol, 1 equiv) in CH₂Cl₂ (6 ml) were added6-bromo-2-pyridinecarbaldehyde (186 mg, 1 mmol, 1 equiv), AcOH (280 μl,5 mmol, 5 equiv)) and NaBH(OAc)₃ (848 mg, 4 mmol, 4 equiv) and theresulting mixture was stirred at room temperature for 1 hour then washedwith a saturated NaHCO₃ aqueous solution, dried over MgSO₄ andconcentrated in vacuo. Purification by flash chromatography on silicagel gave 1,1-dimethylethyl[(1S,2R)-3-[(6-bromo-2-pyridinyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate(H54) (360 mg, 80%) as a white solid. [M+H]⁺=450.4, RT=2.44 min.

BOC-Protected Amines 55-61 (H55-H61)

BOC-protected Amines 55-61 (H55-H61) were obtained in an analogousmanner to that described for BOC-protected Amine 54 using theappropriate aldehyde indicated in the table below (if not commerciallyavailable): Boc-protected amine Aldehyde 1,1-Dimethylethyl[(1S,2R)-3-{[(5-ethenyl-3-thienyl)methyl]amino}-2- D37hydroxy-1-(phenylmethyl)propyl]carbamate (H55) 1,1-Dimethylethyl[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[1-(2,2,2- D43trifluoroethyl)-1H-pyrazol-4-yl]methyl}amino)propyl]carbamate (H56)1,1-Dimethylethyl [(1S,2R)-2-hydroxy-3-[({5-[(methylamino)carbonyl]-3-pyridinyl}methyl)amino]-1-(phenylmethyl)propyl]carbamate (H57)1,1-Dimethylethyl[(1S,2R)-3-[(2,2′-bipyridin-6-ylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamate (H58) 1,1-Dimethylethyl[(1S,2R)-2-hydroxy-3-{[(6-methyl-2-quinoxalinyl)methyl]amino}-1-(phenylmethyl)propyl]carbamate (H59)1,1-Dimethylethyl {(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(3-quinolinylmethyl)amino]propyl}carbamate (H60) 1,1-Dimethylethyl[(1S,2R)-2-hydroxy-3-{[(6-methyl-2-pyridinyl)methyl]amino}-1-(phenylmethyl)propyl]carbamate (H61)BOC-Protected Amine 62

1,1-Dimethylethyl[(1S,2R)-3-{[(5-ethyl-3-thienyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate(H62)

To a solution of 1,1-dimethylethyl[(1S,2R)-3-{[(5-ethenyl-3-thienyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate(H55) (520 mg, 1.3 mmol, 1 equiv) in EtOH (100 ml) at room temperaturewere added 10% Palladium on charcoal (50% wet, 260 mg, 25% w/w) andNH₄COOH (1.6 g, 25.4 mmol, 20 equiv) and the resulting mixture wasstirred at reflux for 2 h then cooled to room temperature. The catalystwas filtered off through a pad of celite and most of the solvent wasremoved. The residue was partitioned between AcOEt and a saturatedNaHCO₃ aqueous solution and the layers were separated. The organic phasewas washed with a saturated NaHCO₃ aqueous solution, dried over MgSO₄and concentrated in vacuo to give 1,1-dimethylethyl[(1S,2R)-3-{[(5-ethyl-3-thienyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate(H62) (410 mg, 79%) as a white solid which was used in the next stepwithout further purification. [M+H]⁺=505.1, RT=2.71 min.

BOC-Protected Amines 63-66 (H63-H66)

BOC-protected amines 63-66 were prepared in an analogous manner to thatdescribed for BOC-protected amine H1, substituting cyclohexylamine withthe appropriate epoxide or amine indicated in the table below (if notcommercially available): Epoxide Amine BOC-protected amine precursorprecursor 1,1-Dimethylethyl [(1S,2R)-2-hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}-1-(phenylmethyl)propyl]carbamate (H63)1,1-Dimethylethyl [(1S,2R)-3-{[(3-ethyl-5-isoxazolyl)methyl] F4amino}-2-hydroxy-1-(phenylmethyl)propyl]carbamate (H64)1,1-Dimethylethyl [(1S,2R)-3-{[(1S)-2-(cyclohexylamino)-1- F5methyl-2-oxoethyl]amino}-2-hydroxy-1-(phenylmethyl)propyl] carbamate(H65) 1,1-Dimethylethyl [(1S,2R)-3-[(4,4-difluorocyclohexyl) amino]- F62-hydroxy-1-(phenylmethyl)propyl]carbamate (H66)Preparation of AcidsAcid 1

7-Ethyl-2-oxo-1,2,3,4-tetrahydro[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid (A1)

To a solution methyl7-ethyl-2-oxo-1,2,3,4-tetrahydro[1,4]diazepino[3,2,1-hi]indole-9-carboxylate(B1) (120 mg, 0.42 mmol, 1 equiv) in EtOH (20 ml) was added 2N aqueousNaOH solution (20 ml, 40 mmol, 95 equiv). The resulting mixture wasstirred for 14 h then most of EtOH was removed in vacuo. The residue wasextracted with Et₂O. The aqueous layer was acidified using 2N aqueousHCl solution and the white precipitate formed was extracted twice withAcOEt. The combined organic solutions were dried over MgSO₄ andconcentrated in vacuo to give7-ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid (A1) (62 mg, 57%) as a white solid, which was used in the next stepwithout further purification. [M+H]⁺=259.4, RT=2.56 min.

Acid 1 (Alternative Procedure)

7-Ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid (A1)

To a solution7-ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid ethyl ester (B18) (120 mg, 0.42 mmol, 1 equiv) in EtOH (20 ml) wasadded 2N aqueous NaOH solution (20 ml, 40 mmol, 95 equiv). The resultingmixture was stirred for 14 h then most of EtOH was removed in vacuo. Theresidue was extracted with Et₂O. The aqueous layer was acidified using2N aqueous HCl solution and the white precipitate formed was extractedtwice with AcOEt. The combined organic solutions were dried over MgSO₄and concentrated in vacuo to give the title compound (A1) (62 mg, 57%)as a white solid, which was used in the next step without furtherpurification. [M+H]⁺=259.4, RT=2.56 min.

Acids 2-17 (A2-A17)

Acids 2-17 were prepared in an analogous manner to that described forAcid 1, from the corresponding esters indicated in the table below: AcidEster [M + H]⁺ RT (min)7-Ethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole- B2 293.22.55 9-carboxylic acid 2,2-dioxide (A2) 7-Ethyl-1-methyl-3,4-dihydro-1H-B3 309.1 2.68 [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid2,2-dioxide (A3) 7-Ethyl-1-phenyl-3,4-dihydro-1H- B4 371.1 3.14[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A4)7-Ethyl-1,3-dimethyl-3,4-dihydro-1H- B5 323.4 2.66[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A5)7-Ethyl-1-(phenylmethyl)-3,4-dihydro-1H- B6 385.4 3.02[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A6)7-Ethyl-1-(1-methylethyl)-3,4-dihydro-1H- B7 337.4 2.80[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A7)1,7-Diethyl-3,4-dihydro-1H- B8 323.4 2.70[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A8)1-Methyl-7-(1-methylethyl)-3,4-dihydro-1H- B9 323.4 2.75[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A9)7-Ethyl-1-(2,2,2-trifluoroethyl)-3,4-dihydro-1H- B10 377.3 2.82[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A10)1-Methyl-7-propyl-3,4-dihydro-1H- B11 323.2 2.74[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A11)1-Ethyl-7-propyl-3,4-dihydro-1H- B12 337.2 2.86[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxylic acid 2,2-dioxide (A12)1-{2-[(1,1-Dimethylethyl)oxy]-2-oxoethyl}-7-ethyl- B13 353.3 (- 2.483,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole- tBu) 9-carboxylicacid 2,2-dioxide (A13) 6-Ethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-B14 279.3 2.45 carboxylic acid 2,2-dioxide (A14)6-Ethyl-1,3-dimethyl-1H-[1,2,5]thiadiazino[3,4,5- B15 309.4 2.80hi]indole-8-carboxylic acid 2,2-dioxide (A15)6-Ethyl-1-methyl-1H-[1,2,5]thiadiazino[3,4,5- B16 295.4 2.70hi]indole-8-carboxylic acid 2,2-dioxide (A16)6-Ethyl-1,3,3-trimethyl-1H-[1,2,5]thiadiazino[3,4,5- B17hi]indole-8-carboxylic acid 2,2-dioxide (A17)Acids 2-4 (A2-A4)

Acids 2-4 were obtained from the corresponding esters using an analogousprocedure to that described for Acid 1 (Alternative Procedure): StartingRT Acid Material [M + H]⁺ (min)2-Ethyl-7,7-dioxo-6,7,8,9-tetrahydro-7/⁶- B19 293.2 2.55thia-6,9a-diaza-benzo[cd]azulene-4- carboxylic acid (A2)2-Ethyl-6-methyl-7,7-dioxo-6,7,8,9- B20 309.1 2.68tetrahydro-7/⁶-thia-6,9a-diaza- benzo[cd]azulene-4-carboxylic acid (A3)2-Ethyl-7,7-dioxo-6-phenyl-6,7,8,9- B21 371.1 3.14tetrahydro-7/⁶-thia-6,9a-diaza- benzo[cd]azulene-4-carboxylic acid (A4)Preparation of AminesAmine 1

(2R,3S)-3-Amino-1-(cyclohexylamino)-4-phenylbutan-2-ol di-hydrochloride(C1)

Tert-butyl[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]carbamate (H1) (9g, 25 mmol, 1 equiv) was dissolved in MeOH (70 ml) and then a 4Msolution of HCl in dioxane (60 ml, excess) was added. The resultingmixture was stirred for 3 h at room temperature and then the solventswere removed by evaporation in vacuo. The resulting residue was washedwith AcOEt and then with Et₂O before drying in vacuo to give(2R,3S)-3-amino-1-(cyclohexylamino)-4-phenylbutan-2-ol di-hydrochloride(C1) as a white solid (7.4 g, 88%).

Amines 2-46 (C2-C46)

Amines 2-46 were prepared in an analogous manner to that described forAmine 1 (C1), from BOC-protected amines H2-H46, respectively. In somecases the 4M HCl in dioxane was replaced with 3 equivalents of p-toluenesulphonic acid to give the tosic acid salts as the product. AminePrecursor (2R,3S)-3-Amino-1-[(3-methoxybenzyl)amino]-4-phenylbutan-2-oldi- H2 tosylate (C2)(2R,3S)-3-Amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2- H3ol di-hydrochloride (C3)(2R,3S)-3-Amino-1-{[1-(3-methoxyphenyl)-1-methylethyl]amino}-4- H4phenylbutan-2-ol di-hydrochloride (C4)(2R,3S)-3-Amino-1-({1-methyl-1-[3- H5(trifluoromethyl)phenyl]ethyl}amino)-4-phenylbutan-2-ol di-hydrochloride (C5)(2R,3S)-3-Amino-4-phenyl-1-{[3-(trifluoromethoxy)benzyl]amino}butan- H62-ol di-tosylate (C6) (2R,3S)-3-Amino-1-(benzylamino)-4-phenylbutan-2-oldi-tosylate (C7) H7(2R,3S)-3-Amino-1-[(2-methylbenzyl)amino]-4-phenylbutan-2-ol di- H8tosylate (C8)(2R,3S)-3-Amino-1-[(3-methylbenzyl)amino]-4-phenylbutan-2-ol di- H9tosylate (C9)(2R,3S)-3-Amino-1-[(4-methylbenzyl)amino]-4-phenylbutan-2-ol di- H10tosylate (C10)(2R,3S)-3-Amino-4-phenyl-1-[(pyridin-2-ylmethyl)amino]butan-2-ol tri-H11 tosylate (C11)(2R,3S)-3-Amino-4-phenyl-1-[(pyridin-3-ylmethyl)amino]butan-2-ol di- H12tosylate (C12)(2R,3S)-3-Amino-4-phenyl-1-[(pyridin-4-ylmethyl)amino]butan-2-ol di- H13tosylate (C13)(2R,3S)-3-Amino-4-phenyl-1-[(2-phenylethyl)amino]butan-2-ol di- H14tosylate (C14)(2R,3S)-3-Amino-4-phenyl-1-(tetrahydro-2H-pyran-4-ylamino)butan-2- H15ol di-hydrochloride (C15)(2R,3S)-3-Amino-1-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-4- H16phenylbutan-2-ol di-tosylate (C16)(2R,3S)-3-Amino-4-phenyl-1-[(1,1,5-trimethylhexyl)amino]butan-2-ol di-H17 hydrochloride (C17)(2R,3S)-3-Amino-1-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-4- H18phenylbutan-2-ol di-tosylate (C18)(2R,3S)-3-Amino-1-[(2-methoxyethyl)amino]-4-phenylbutan-2-ol di- H19tosylate (C19) (2R,3S)-3-Amino-1-ethylamino-4-phenylbutan-2-oldi-tosylate (C20) H20(2R,3S)-3-Amino-1-[(2-fluoroethyl)amino]-4-phenylbutan-2-ol di- H21tosylate (C21)(2R,3S)-3-Amino-1-[(2,2-difluoroethyl)amino]-4-phenylbutan-2-ol di- H22tosylate (C22)(2R,3S)-3-Amino-4-phenyl-1-[(2,2,2-trifluoroethyl)amino]butan-2-ol di-H23 tosylate (C23) (2R,3S)-3-Amino-4-phenyl-1-(propylamino)butan-2-oldi-tosylate (C24) H24(2R,3S)-3-Amino-1-(isopropylamino)-4-phenylbutan-2-ol di-tosylate H25(C25) (2R,3S)-3-Amino-1-(cyclopropylamino)-4-phenylbutan-2-oldi-tosylate H26 (C26)(2R,3S)-3-Amino-1-[(2,2,3,3,3-pentafluoropropyl)amino]-4- H27phenylbutan-2-ol di-tosylate (C27)(2R,3S)-3-Amino-4-phenyl-1-(prop-2-yn-1-ylamino)butan-2-ol di- H28tosylate (C28) (2R,3S)-3-Amino-1-(butylamino)-4-phenylbutan-2-oldi-tosylate (C29) H29(2R,3S)-3-Amino-1-{[(1S)-1-methylpropyl]amino}-4-phenylbutan-2-ol H30di-tosylate (C30)(2R,3S)-3-Amino-1-{[(1R)-1-methylpropyl]amino}-4-phenylbutan-2-ol H31di-tosylate (C31)(2R,3S)-3-Amino-1-[(cyclopropylmethyl)amino]-4-phenylbutan-2-ol di- H32tosylate (C32) (2R,3S)-3-Amino-1-(isobutylamino)-4-phenylbutan-2-oldi-tosylate H33 (C33)(2R,3S)-3-Amino-1-(cyclobutylamino)-4-phenylbutan-2-ol di-tosylate H34(C34) (2R,3S)-3-Amino-1-(tert-butylamino)-4-phenylbutan-2-ol di-tosylateH35 (C35) (2R,3S)-3-Amino-1-(cyclopentylamino)-4-phenylbutan-2-oldi-tosylate H36 (C36)(2R,3S)-3-Amino-1-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)amino]-4- H37phenyl-2-butanol di-tosylate (C37)(2R,3S)-3-Amino-4-(3-chlorophenyl)-1-(cyclopropylamino)-2-butanol H38di-tosylate (C38)(2R,3S)-3-Amino-4-(3-chlorophenyl)-1-(cyclohexylamino)-2-butanol di- H39tosylate (C39)(2R,3S)-3-Amino-4-(3-chlorophenyl)-1-(tetrahydro-2H-pyran-4- H40ylamino)-2-butanol di-tosylate (C40)(2R,3S)-3-Amino-1-(cyclopropylamino)-4-(3-fluorophenyl)-2-butanol di-H41 tosylate (C41)(2R,3S)-3-Amino-1-(cyclohexylamino)-4-(3-fluorophenyl)-2-butanol di- H42tosylate (C42)(2R,3S)-3-Amino-4-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-4- H43ylamino)-2-butanol di-tosylate (C43)(2R,3S)-3-Amino-1-(cyclopropylamino)-4-(3,5-difluorophenyl)-2- H44butanol di-tosylate (C44)(2R,3S)-3-Amino-1-(cyclohexylamino)-4-(3,5-difluorophenyl)-2-butanol H45di-tosylate (C45)(2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-4- H46ylamino)-2-butanol di-tosylate (C46)Amines 50-52 (C50-C52)

Amines 50-52 were obtained in an analogous procedure to that describedfor Amine 53 (C53) from BOC-protected amines H50-H52, respectively: RTAmine Precursor [M + H]⁺ (min) Phenylmethyl [(2R,3S)-3-amino-4-(3- H50363.4 2.27 chlorophenyl)-2- hydroxybutyl]methylcarbamate hydrochloride(C50) Phenylmethyl [(2R,3S)-3-amino-4-(3- H51 347.5 2.05fluorophenyl)-2- hydroxybutyl]methylcarbamate hydrochloride (C51)Phenylmethyl [(2R,3S)-3-amino-2- H52 — — hydroxy-4-phenylbutyl]methylcarbamate hydrochloride (C52)

Phenylmethyl [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbamatehydrochloride (C53)

A solution of 1,1-dimethylethyl[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[(phenylmethyl)oxy]carbonyl}amino)propyl]carbamate(H53) (31.5 g, 76.1 mmol, 1 equiv) in THF (300 ml) was treated with 4NHCl solution in dioxan (40 ml, 160 mmol, 2.1 equiv). The resultingsolution was stirred at room temperature for 2 h then concentrated invacuo. The residue was tritureated with Et₂O/iso-hexane to givephenylmethyl [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbamatehydrochloride (C53) (22.1 g, 83%) as a white solid which was used in thenext step without further purification.

Amines 54 and 56-66 (C54 and C56-C66)

Amines 54 and 56-66 were prepared in an analogous manner to thatdescribed for Amine 1 (C1), substituting the appropriate BOC-protectedamines for tert-butyl[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]carbamate. In somecases the 4M HCl in dioxane was replaced with 3 equivalents of p-toluenesulphonic acid to give the tosic acid salts as the product. AminePrecursor(2R,3S)-3-Amino-1-{[(6-bromo-2-pyridinyl)methyl]amino}-4-phenyl-2- H54butanol (C54)(2R,3S)-3-Amino-4-phenyl-1-({[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- H56yl]methyl}amino)-2-butanol di-tosylate (C56)5-({[(2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl]amino}methyl)-N-methyl- H573-pyridinecarboxamide di-tosylate (C57)(2R,3S)-3-Amino-1-[(2,2′-bipyridin-6-ylmethyl)amino]-4-phenyl-2- H58butanol di-tosylate (C58)(2R,3S)-3-Amino-1-{[(6-methyl-2-quinoxalinyl)methyl]amino}-4-phenyl- H592-butanol di-tosylate (C59)(2R,3S)-3-Amino-4-phenyl-1-[(3-quinolinylmethyl)amino]-2-butanol di- H60tosylate (C60)(2R,3S)-3-Amino-1-{[(6-methyl-2-pyridinyl)methyl]amino}-4-phenyl-2- H61butanol di-tosylate (C61)(2R,3S)-3-Amino-1-{[(5-ethyl-3-thienyl)methyl]amino}-4-phenyl-2- H62butanol di-tosylate (C62)(2R,3S)-3-Amino-1-{[(5-methyl-2-pyrazinyl)methyl]amino}-4-phenyl-2- H63butanol di-hydrochloride (C63)(2R,3S)-3-Amino-1-{[(3-ethyl-5-isoxazolyl)methyl]amino}-4-phenyl-2- H64butanol di-tosylate (C64)N²-[(2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl]-N¹-cyclohexyl-L- H65alaninamide di-hydrochloride (C65)(2R,3S)-3-Amino-1-[(4,4-difluorocyclohexyl)amino]-4-phenyl-2-butanol H66(C66)

PREPARATION OF EXAMPLES Example 17-Ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-amide(E1)

To a solution of7-ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid (A1) (31 mg, 0.12 mmol, 1 equiv) in DMF (2 ml) and CH₂Cl₂ (8 ml) atroom temperature was added(2R,3S)-3-amino-1-(3-methoxy-benzylamino)-4-phenyl-butan-2-oldi-tosylate (C2) (77 mg, 0,12 mmol, 1 equiv),1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (28 mg,0.15 mmol, 1.2 equiv), 1-hydroxybenzotriazole hydrate (22 mg, 0.15 mmol,1.2 equiv) and 4-ethylmorpholine (34 μl, 0.27 mmol, 2.2 equiv). Theresulting mixture was stirred for 4 h then a saturated aqueous NaHCO₃solution (10 ml) was added. The resulting mixture was vigorously stirredfor 20 min. The layers were separated through an hydrophobic frit andthe organic phase was concentrated in vacuo. The residue was purified bytrituration with Et₂O to yield7-ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-amide(E1) as a white solid (43.5 mg, 67%). [M+H]⁺=541.5, RT=2.51 min.

Examples 2-88 (E2-E88)

Examples 2-88 were obtained in an analogous manner to the proceduredescribed for Example 1 using the appropriate acid and the appropriateamine: RT Example Structure Acid Amine [M + H]⁺ (min)7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide (E2)

A2 C2 577.4 2.52 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide (E3)

A3 C2 591.4 2.6 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-phenyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide (E4)

A4 C2 653.3 2.85 7-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino [3,4,5-hi]indole-9-carboxamide2,2-dioxide formate salt (E5)

A3 C3 629.5 2.69 7-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino [3,4,5-hi]indole-9-carboxamide2,2-dioxide formate salt (E6)

A5 C3 643.5 2.78 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E7)

A3 C1 553.5 2.42 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1,3- dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E8)

A5 C1 567.6 2.61 7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5- trimethylhexyl)amino]propyl}-1,3-dimethyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E9)

A5 C17 611.7 2.99 7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5- trimethylhexyl)amino]propyl}-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E10)

A3 C17 597.6 2.88 7-Ethyl-N-[(1S,2R)-2-hydroxy-3- ({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-1-(phenylmethyl) propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E11)

A3 C5 657.5 2.81 7-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-(phenylmethyl)-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E12)

A6 C3 705.5 3.02 7-Ethyl-N-[(1S,2R)-2-hydroxy-3- ({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)- 1-(phenylmethyl)propyl]-1,3-dimethyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E13)

A5 C4 633.6 2.64 7-Ethyl-N-[(1S,2R)-2-hydroxy-3- ({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)- 1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E14)

A3 C4 619.6 2.6 7-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E15)

A3 C18 579.6 2.34 7-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-1,3-dimethyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E16)

A5 C18 593.6 2.43 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(1-methylethyl)amino]-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E17)

A3 C25 513.5 2.28 7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E18)

A3 C15 555.6 2.28 N-[(1S,2R)-3-(Cyclopropylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E19)

A3 C26 511.5 2.26 7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1-(1-methylethyl)-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E20)

A7 C15 538.5 2.41 1,7-Diethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro- 2H-pyran-4-ylamino)propyl]-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E21)

A8 C15 569.5 2.36 N-[(1S,2R)-2-Hydroxy-3-[(1- methylethyl)amino]-1-(phenylmethyl)propyl]-1-methyl-7- (1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E22)

A9 C25 527.5 2.47 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7- (1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E23)

A9 C1 567.5 2.67 N-[(1S,2R)-3-(Cyclopropylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7- (1-methylethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E24)

A9 C26 525.5 2.46 N-[(1S,2R)-2-Hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1-methyl-7-(1-methylethyl)-3,4- dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E25)

A9 C15 569.5 2.39 N-[(1S,2R)-2-Hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl) propyl]-1-methyl-7-(1-methylethyl)-3,4- dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E26)

A9 C2 605.5 2.66 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-1,7-diethyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E27)

A8 C1 567.5 2.55 7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(2,2,2- trifluoroethyl)amino]propyl}-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E28)

A3 C23 553.4 2.8 7-Ethyl-N-[(1S,2R)-2-hydroxy-3- [(2,2,3,3,3-pentafluoropropyl)amino]-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E29)

A3 C27 603.4 2.95 N-[(1S,2R)-3- [(Cyclopropylmethyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]- 7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E30)

A3 C32 525.5 2.28 N-[(1S,2R)-1-[(3- Chlorophenyl)methyl]-3-(cyclopropylamino)-2- hydroxypropyl]-7-ethyl-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E31)

A3 C38 545.2 2.33 N-[(1S,2R)-1-[(3- Chlorophenyl)methyl]-3-(cyclohexylamino)-2- hydroxypropyl]-7-ethyl-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E32)

A3 C39 587.5 2.53 N-[(1S,2R)-1-[(3- Chlorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran-4- ylamino)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E33)

A3 C40 589.4 2.34 N-{(1S,2R)-3- (Cyclopropylamino)-1-[(3-fluorophenyl)methyl]-2- hydroxypropyl}-7-ethyl-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E34)

A3 C41 529.4 2.26 7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1-(2,2,2-trifluoroethyl)-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E35)

A10 C15 623.4 2.45 N-{(1S,2R)-3-(Cyclohexylamino)-1-[(3-fluorophenyl)methyl]-2- hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E36)

A3 C42 571.5 2.51 7-Ethyl-N-[(1S,2R)-1-[(3-fluorophenyl)methyl]-2-hydroxy-3- (tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-3,4- dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E37)

A3 C43 573.4 2.33 N-{(1S,2R)-3-(Cyclohexylamino)-1-[(3,5-difluorophenyl)methyl]-2- hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E38)

A3 C45 589.4 2.65 N-{(1S,2R)-3- (Cyclopropylamino)-1-[(3,5-difluorophenyl)methyl]-2- hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E39)

A3 C44 547.3 2.44 N-[(1S,2R)-3-(Cyclobutylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E40)

A3 C34 525.3 2.38 7-Ethyl-N-[(1S,2R)-3-[(2-fluoroethyl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E41)

A3 C21 517.5 2.16 N-[(1S,2R)-3-[(2,2- Dimethyltetrahydro-2H-pyran-4-yl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide (E42)

A3 C37 583.5 2.44 N-[(1S,2R)-3-[(1,1- Dimethylethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl- 1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E43)

A3 C35 527.6 2.41 N-[(1S,2R)-2-Hydroxy-1- (phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}am ino)propyl]-1-methyl-7-propyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E44)

A11 C3 643.4 2.88 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7- propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E45)

A11 C1 567.4 2.66 N-[(1S,2R)-2-Hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1-methyl-7-propyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E46)

A11 C15 569.4 2.43 N-[(1S,2R)-3-{[(1-Ethyl-1H-pyrazol-4-yl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-1-methyl-7-propyl-3,4-dihydro- 1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E47)

A11 C18 593.4 2.47 1-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3- (trifluoromethyl)phenyl]methyl}amino)propyl]-7-propyl-3,4-dihydro- 1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E48)

A12 C3 657.4 2.94 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-1-ethyl-7- propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E49)

A12 C1 581.4 2.73 1-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-7-propyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E50)

A12 C15 583.4 2.49 1-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-7-propyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E51)

A12 C18 607.4 2.53 N-[(1S,2R)-1-[(3,5- Difluorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran- 4-ylamino)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E52)

A3 C46 591.3 2.41 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[2-(methyloxy)ethyl]amino}-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E53)

A3 C19 529.5 2.28 7-Ethyl-N-[(1S,2R)-3- (ethylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E54)

A3 C20 499.5 2.3 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(1S)-1-methylpropyl]amino}-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E55)

A3 C30 527.5 2.42 N-[(1S,2R)-3-(Butylamino)-2-hydroxy-1-(phenylmethyl)propyl]- 7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E56)

A3 C29 527.5 2.5 7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(2-propyn-1- ylamino)propyl]-1-methyl-3,4- dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E57)

A3 C28 509.2 2.29 N-[(1S,2R)-3-(Cyclopentylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E58)

A3 C36 539.3 2.42 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide (E59)

A3 C33 527.3 2.42 7-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-(propylamino)propyl]-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E60)

A3 C24 513.3 2.35 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(1R)-1-methylpropyl]amino}-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide (E61)

A3 C31 527.3 2.42 N-[(1S,2R)-3-[(2,2- Difluoroethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide (E62)

A3 C22 535.3 2.35 7-Ethyl-N-{(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-[(phenylmethyl)amino]propyl}-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E63)

A3 C7 561.6 2.6 7-Ethyl-N-{(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-[(2-pyridinylmethyl)amino]propyl}-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E64)

A3 C11 562.6 2.44 7-Ethyl-N-{(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-[(4-pyridinylmethyl)amino]propyl}-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E65)

A3 C13 562.6 2.35 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(2-phenylethyl)amino]-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E66)

A3 C14 575.4 2.64 7-Ethyl-N-{(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-[({3-[(trifluoromethyl)oxy]phenyl}methyl)amino]propyl}-1-methyl3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E67)

A3 C6 645.4 2.81 7-Ethyl-N-{(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-[(3-pyridinylmethyl)amino]propyl}-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E68)

A3 C12 562.6 2.35 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(2-methylphenyl)methyl]amino}- 1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E69)

A3 C8 575.4 2.6 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(3-methylphenyl)methyl]amino}- 1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E70)

A3 C9 575.4 2.62 7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(4-methylphenyl)methyl]amino}- 1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formate salt (E71)

A3 C10 575.4 2.62 N-[(1S,2R)-3-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-2-hydroxy-1- (phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E72)

A3 C16 587.3 2.58 1,1-Dimethylethyl [7-ethyl-9- ({[(1S,2R,)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]acetate formate salt (E73)

A13 C3 — 2.7 7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-yl]methyl}amino)propyl]-1-methyl- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E74)

A3 C56 633.4 2.48 6-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5- trimethylhexyl)amino]propyl}-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E75)

A14 C17 569.6 2.78 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-6-ethyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide 2,2-dioxide formate salt (E76)

A14 C1 525.5 2.39 6-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E77)

A14 C3 601.5 2.6 6-Ethyl-N-[(1S,2R)-2-hydroxy-1- (phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1,3dimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E78)

A15 C3 629.5 2.87 6-Ethyl-N-[(1S,2R)-2-hydroxy-3- ({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1-methyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide2,2-dioxide formate salt (E79)

A16 C5 643.6 2.85 N-[(1S,2R)-3-(Cyclohexylamino)- 2-hydroxy-1-(phenylmethyl)propyl]-6-ethyl-1- methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E80)

A16 C1 539.6 2.55 6-Ethyl-N-[(1S,2R)-2-hydroxy-3- ({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)- 1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5- hi]indole-8-carboxamide 2,2- dioxideformate salt (E81)

A16 C4 605.6 2.69 6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1- methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E82)

A16 C15 514.6 2.33 6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E83)

A16 C3 615.5 2.78 6-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5- trimethylhexyl)amino]propyl}-1- methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide 2,2-dioxide formatesalt (E84)

A16 C17 583.6 2.99 6-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(1-methylethyl)amino]-1- (phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5- hi]indole-8-carboxamide 2,2- dioxideformate salt (E85)

A16 C25 499.5 2.38 6-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl] methyl}amino)-1-(phenylmethyl)propyl]-1-methyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide2,2-dioxide formate salt (E86)

A16 C2 577.6 2.64 6-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-1-methyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide2,2-dioxide formate salt (E87)

A16 C18 565.6 2.38 6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H- pyran-4-ylamino)propyl]-1,3,3-trimethyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole- 8-carboxamide2,2-dioxide formate salt (E88)

A17 C15 569.5 2.53

Example 89N-[(1S,2R)-3-Amino-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide (E89)

To a solution of phenylmethyl((2R,3S)-3-{[(7-ethyl-1-methyl-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-9-yl)carbonyl]amino}-2-hydroxy-4-phenylbutyl)carbamate(D24) (1.35 g, 2.27 mmol, 1 equiv) in AcOEt (20 ml) was added 10%Palladium on charcoal (50% wet, 270 mg, 10% w/w) and the resultingmixture was stirred at room temperature under an atmosphere of hydrogenfor 2 h. The catalyst was filtered off through a pad of celite and thesolution concentrated in vacuo to giveN-[(1S,2R)-3-amino-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide (E89) (900 mg, 90%) as a white foam. [M+H]⁺=471.4, RT=2.14min.

Examples 90-94 (E90-E94)

Examples 90-94 were obtained using an analogous procedure to thatdescribed in Example 89 from the appropriate precursor indicated in thetable below: RT Example Structure Precursor [M + H]⁺ (min)7-Ethyl-N-[(1S,2R)-2- hydroxy-3-(methylamino)-1-(phenylmethyl)propyl]-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formatesalt (E90)

D22 485.5 2.24 N-[(1S,2R)-2-Hydroxy-3- (methylamino)-1-(phenylmethyl)propyl]-1- methyl-7-(1-methylethyl)- 3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formatesalt (E91)

D23 499.5 2.37 N-[(1S,2R)-1-[(3- Chlorophenyl)methyl]-2- hydroxy-3-(methylamino)propyl]-7- ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino [3,4,5-hi]indole-9- carboxamide 2,2-dioxideformate salt (E92)

D20 519.4 2.30 7-Ethyl-N-[(1S,2R)-1-[(3- fluorophenyl)methyl]-2-hydroxy-3-(methylamino) propyl]-1-methyl-3,4- dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2-dioxide formatesalt (E93)

D21 503.5 2.26 6-Ethyl-N-[(1S,2R)-2- hydroxy-3-(methylamino)-1-(phenylmethyl)propyl]-1- methyl-1H- [1,2,5]thiadiazino[3,4,5-hi]indole-9-carboxamide 2,2-dioxide (E94)

D25 471.5 2.29

Example 95[7-Ethyl-9-({[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]aceticacid (E95)

To a solution of 1,1-dimethylethyl[7-ethyl-9-({[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]acetateformate salt (E73) (10 mg) in CH₂Cl₂ (1 ml) was added TFA (1 ml) and theresulting solution was stirred at room temperature for 1 h thenconcentrated in vacuo. Trituration of the residue with Et₂O gave[7-ethyl-9-({[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]aceticacid (E95) (5 mg, 50%) as a white solid. [M+H]+=673.3, RT=2.71 min.

Examples 96-106 (E96-E106)

Examples 96-106 were obtained in an analogous manner to Example 1 (E1)using the appropriate acid and the appropriate amine indicated in thetable below: RT Example Structure Acid Amine [M + H]⁺ (min)N-[(1S,2R)-3-{[(6-Bromo-2- pyridinyl)methyl]amino}-2- hydroxy-1-(phenylmethyl)propyl]-7- ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxideformate salt (E96)

A3 C54 640.4 2.64 7-Ethyl-N-[(1S,2R)-2 hydroxy-3-[({5-[(methylamino)carbonyl]-3- pyridinyl}methyl)amino]-1-(phenylmethyl)propyl]-1- methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E97)

A3 C57 619.4 2.31 N-[(1S,2R)-3-[(2,2′-Bipyridin- 6-ylmethyl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-7- ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxideformate salt (E98)

A3 C58 639.5 2.59 7-Ethyl-N-[(1S,2R)-2- hydroxy-3-{[(6-methyl-2-quinoxalinyl)methyl]amino}- 1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E99)

A3 C59 627.5 2.61 7-Ethyl-N-{(1S,2R)-2- hydroxy-1-(phenylmethyl)-3-[(3-quinolinylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5- hi]-indole-9-carboxamide 2,2- dioxideformate salt (E100)

A3 C60 612.5 2.58 7-Ethyl-N-[(1S,2R)-2- hydroxy-3-{[(6-methyl-2-pyridinyl)methyl]amino}-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E101)

A3 C61 576.5 2.54 7-Ethyl-N-[(1S,2R)-3-{[(5- ethyl-3-thienyl)methyl]amino}-2- hydroxy-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E102)

A3 C62 595.2 2.79 7-Ethyl-N-[(1S,2R)-2- hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide formate salt (E103)

A3 C63 577.5 2.41 7-Ethyl-N-[(1S,2R)-3-{[(3- ethyl-5-isoxazolyl)methyl]amino}-2- hydroxy-1- (phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide (E104)

A3 C64 580.5 2.57 N-[(1S,2R)-3-{[(1S)-2- (Cyclohexylamino)-1-methyl-2-oxoethyl]amino}-2- hydroxy-1- (phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro- 1H- [1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2- dioxide (E105)

A3 C65 624.5 2.65 N-[(1S,2R)-3-[(4,4- Difluorocyclohexyl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-7- ethyl-1-methyl-3,4-dihydro- 1H-[1,2,5]thiadiazepino[3,4,5- hi]indole-9-carboxamide 2,2- dioxide formatesalt (E106)

A3 C66 589.5 2.52

Compounds of the invention may be tested for in vitro biologicalactivity in accordance with the following assays:

(I) Asp-2 Inhibitory Assay

For each compound being assayed, in a 384 well plate, is added:

a) 1 μl of a DMSO solution of the test compound (IC₅₀ curve uses ten 1in 2 serial dilutions from 500 μM).

b) 10 μl of substrate (FAM-[SEVNLDAEFK]-TAMRA) solution in buffer. Thisis prepared by diluting 2 ml of a 2 mM DMSO solution of the substrateinto 400 ml of buffer (100 mM Sodium acetate pH=4.5, 1 l Milli-Q water,0.06% Triton X-100 (0.5 ml/l), pH adjusted to 4.5 using glacial aceticacid). Aminomethyl fluorescein (FAM) and tetramethyl rhodamine (TAMRA)are fluorescent molecules which co-operate to emit fluorescence at 535nm upon cleavage of the SEVNLDAEFK peptide.

c) 10 μl enzyme solution. This is prepared by diluting 16 ml of a 500 nMenzyme solution into 384 ml of buffer (prepared as above).

Blank wells (enzyme solution replaced by buffer) are included ascontrols on each plate. Wells are incubated for 1 h at room temperatureand fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer(485 nm excitation, 535 nm emission).

(II) Cathepsin D Inhibitory Assay

For each compound being assayed, in a 384 well plate, is added:

a) 1 μl of a DMSO solution of the test compound (IC₅₀ curve uses ten 1in 2 serial dilutions from 500 μM).

b) 10 μl of substrate (FAM-[SEVNLDAEFK]-TAMRA) solution in buffer. Thisis prepared by diluting 2 ml of a 2 mM DMSO solution of the substrateinto 400 ml of buffer (100 mM Sodium acetate pH=4.5, 1 l Milli-Q water,0.06% Triton X-100 (0.5 ml/l), pH adjusted to 4.5 using glacial aceticacid).

c) 10 μl enzyme solution. This is prepared by diluting 1.6 ml of a 200unit/ml (in 10 mM HCl) enzyme solution into 398.4 ml of buffer (preparedas above).

Blank wells (enzyme solution replaced by buffer) are included ascontrols on each plate. Wells are incubated for I h at room temperatureand fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer(485 nm excitation, 535 nm emission).

Pharmacological Data

The compounds of E1-E106 were tested in the Asp-2 inhibitory assay andexhibited inhibition <10 μM. More particularly, the compounds ofExamples E3-E7, E9-E11, E13, E15-E16, E21, E27, E32, E36, E37-E39, E44,E47-E48, E51, E67, E70, E72, E74, E78-E79, E83, E86, E97, E102, E104 andE105-E106 exhibited inhibition <1 μM in the Asp-2 inhibitory assay. Mostparticularly, the compounds of Examples E3, E5, E15-E16, E39, E47, E51,E67, E70, E74, E97, E102, E104 and E105 were tested in the Asp-2inhibitory assay and the Cathepsin D inhibitory assay and exhibitedinhibition <1 μM in the Asp-2 inhibitory assay and >100 fold selectivityfor Asp2 over CatD.

Abbreviations

DMF dimethylformamide

DMSO dimethylsulfoxide

DMAP dimethylaminophenol

DABCO 1,4diazabicyclo [2.2.2] octane

DME dimethyl ether

THF tetrahydrofuran

HOBT N-hydroxybenzotriazole

FAM carboxyfluorescein

TAMRA carboxytetramethylrhodamine

[ ] single amino acid letter code relating to peptide sequence

1-8. (canceled)
 9. A compound of formula (I):

wherein R¹ and R² independently represent C₁₋₃ alkyl, C₂₋₄ alkenyl,halogen, C₁₋₃ alkoxy, amino, cyano, or hydroxy; m and n independentlyrepresent 0, 1, or 2; p represents 1 or 2; A-B represents —NR⁵—SO₂— or—NR⁵—CO—; R⁵ represents hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, arylC₁₋₆ alkyl-,heteroarylC₁₋₆ alkyl-, arylC₃₋₈ cycloalkyl-, or heteroarylC₃₋₈cycloalkyl-; X—Y-Z represents —N—CR⁸═CR⁹—; R⁸ represents hydrogen, C₁₋₆alkyl, or C₃₋₈ cycloalkyl; R⁹ represents hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, aryl, heteroaryl, arylC₁₋₆ alkyl-, heteroarylC₁₋₆ alkyl-,arylC₃₋₈ cycloalkyl-, heteroarylC₃₋₈ cycloalkyl-, —COOR¹⁰, —OR¹⁰,—CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, —COC₁₋₆ alkyl, or —SO₂C₁₋₆ alkyl (wherein R¹⁰and R¹¹ independently represent hydrogen, C₁₋₆ alkyl, or C₃₋₈cycloalkyl); R³ represents optionally substituted C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-aryl,—C₁₋₆ alkyl-heteroaryl, or —C₁₋₆ alkyl-heterocyclyl; R⁴ representshydrogen, optionally substituted C₁₋₁₀ alkyl, C₂₋₆ alkynyl, —C₃₋₈cycloalkyl, —C₃₋₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, —C₃₋₈ cycloalkyl-aryl, -heterocyclyl-aryl, —C₁₋₆alkyl-aryl-heteroaryl, —C(R^(a)R^(b))—CONH—C₁₋₆ alkyl,—C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, —C₁₋₆alkyl-NR^(c)R^(d), —C(R^(a)R^(b))—C₁₋₆ alkyl, —C(R^(a)R^(b))-aryl,—C(R^(a)R^(b))-heteroaryl, —C(R^(a)R^(b))-herteroaryl-heteroaryl,—C(R^(a)R^(b))—C₁₋₆ alkyl-aryl, —C(R^(a)R^(b))—C₁₋₆ alkyl-heteroaryl,—C(R^(a)R^(b))—C₁₋₆ alkyl-heterocyclyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl-aryl,—C₁₋₆ alkyl-O—C₁₋₆ alkyl-heteroaryl, or —C₁₋₆ alkyl-O—C₁₋₆alkyl-heterocyclyl; R^(a) and R^(b) independently represent hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₈ cycloalkyl, or R^(a) andR^(b) together with the carbon atom to which they are attached may forma C₃₋₈ cycloalkyl or heterocyclyl group; R^(c) and R^(d) independentlyrepresent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, or R^(c) and R^(d) together with the nitrogen atom to whichthey are attached may form a nitrogen containing heterocyclyl group;wherein said aryl, heteroaryl, or heterocyclyl groups of R³—R⁵, R⁹ andR^(a)—R^(d) may be optionally substituted by one or more C₁₋₆ alkyl,halogen, haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, oxo, C₁₋₆ alkoxy, C₂₋₆alkynyl, C₂₋₆ alkenyl, amino, cyano, nitro, —NR²²COR²³,—CONR²²R²³—SO₂R²², —SO₂NR²²R²³,—COOR²², —C₁₋₆ alkyl-NR²²R²³ (wherein R²²and R²³ independently represent hydrogen, C₁₋₆ alkyl or C₃₋₈cycloalkyl), —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkanoyl, or hydroxygroups; and wherein said alkyl and cycloalkyl groups of R¹—R⁵, R⁸—R¹¹,R²²—R²³ and R^(a)—R^(d) may be optionally substituted by one or morehalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, amino, cyano,hydroxy, carboxy, or —COOC₁₋₆ alkyl groups; or a pharmaceuticallyacceptable salt or solvate thereof.
 10. A compound according to claim 9,wherein A-B represents —NR⁵—SO₂—.
 11. A compound according to claim 9,wherein R⁵ represents: hydrogen; C₁₋₆ alkyl optionally substituted byone or more halogen atoms, carboxy or —COOC₁₋₆ alkyl groups; aryl; orarylC₁₋₆ alkyl-.
 12. A compound according to claim 9, wherein m and nrepresent
 0. 13. A compound according to claim 9, wherein p represents2.
 14. A compound according to claim 9, wherein R⁸ represents hydrogenand wherein R⁹ represents hydrogen or C₁₋₆ alkyl.
 15. A compoundaccording to claim 9, wherein R³ represents —C₁₋₆ alkyl-aryl optionallysubstituted by one or two halogen atoms.
 16. A compound according toclaim 9, wherein R⁴ represents -hydrogen; —C₁₋₁₀ alkyl optionallysubstituted by one or more halogen or C₁₋₆ alkoxy groups; C₂₋₆ alkynyl;—C₃₋₈ cycloalkyl optionally substituted by one or more halogen atoms orC₁₋₆ alkyl groups; —C₁₋₆ alkyl-C₃₋₈ cycloalkyl; aryl; -heterocyclyl;—C(R^(a)R^(b))-aryl optionally substituted by one or more halogen,cyano, nitro, haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkyl or C₁₋₆alkoxy, C₂₋₆ alkynyl, C₂₋₆ alkenyl, amino, —NR²²COR²³,—CONR²²R²³—SO₂R²², —SO₂NR²²R²³, —COOR², C₁₋₆ alkyl-NR²²R²³, —C₁₋₆alkanoyl, or hydroxy groups; —C(R^(a)R^(b))-heteroaryl optionallysubstituted by one or more C₁₋₆ alkyl, halogen, haloC₁₋₆ alkyl, or—CONR²²R²³ groups; —C(R^(a)R^(b))-heteroaryl-heteroaryl;—C(R^(a)R^(b))—C₁₋₆ alkyl-aryl; —C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl; or—C₃₋₈ cycloalkyl-aryl.
 17. A compound according to claim 16, wherein R⁴represents: —C₃₋₈ cycloalkyl optionally substituted by one or morehalogen atoms; -heterocyclyl; —C(R^(a)R^(b))-aryl optionally substitutedby one or more haloC₁₋₆ alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkyl, or C₁₋₆alkoxy groups; —C(R^(a)R^(b))-heteroaryl optionally substituted by oneor more C₁₋₆ alkyl, haloC₁₋₆ alkyl, or —CONR²²R²³ groups; or—C(R^(a)R^(b))—CONH—C₃₋₈ cycloalkyl.
 18. A compound according to claim9, wherein R^(a) and R^(b) independently represent hydrogen or methyl,or R^(a) and R^(b) together with the carbon atom to which they areattached form a cyclopropyl or cyclohexyl group.
 19. A compoundaccording to claim 9 which is:7-Ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[3,2,1-hi]indole-9-carboxylicacid[(1S,2R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-amide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-phenyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5-trimethylhexyl)amino]propyl}-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5-trimethylhexyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-(phenylmethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1,3-dimethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(1-methylethyl)amino]-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclopropylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;1,7-Diethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-3-[(1-methylethyl)amino]-1-(phenylmethyl)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclopropylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1,7-diethyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(2,2,2-trifluoroethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(2,2,3,3,3-pentafluoropropyl)amino]-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(Cyclopropylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-1-[(Chlorophenyl)methyl]-3-(cyclopropylamino)-2-hydroxypropyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-1-[(3-Chlorophenyl)methyl]-3-(cyclohexylamino)-2-hydroxypropyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-1-[(3-Chlorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-{(1S,2R)-3-(Cyclopropylamino)-1-[(3-fluorophenyl)methyl]-2-hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-{(1S,2R)-3-(Cyclohexylamino)-1-[(3-fluorophenyl)methyl]-2-hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-1-[(3-fluorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-{(1S,2R)-3-(Cyclohexylamino)-1-[(3,5-difluorophenyl)methyl]-2-hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-{(1S,2R)-3-(Cyclopropylamino)-1-[(3,5-difluorophenyl)methyl]-2-hydroxypropyl}-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclobutylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-3-[(2-fluoroethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(2,2-Dimethyltetrahydro-2H-pyran4-yl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(1,1-Dimethylethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-methyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-{[(1-Ethyl-1H-pyrazol4-yl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;1-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-ethyl-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;1-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;1-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-7-propyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-1-[(3,5-Difluorophenyl)methyl]-2-hydroxy-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[2-(methyloxy)ethyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-3-(ethylamino)-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(1S)-1-methylpropyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Butylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(2-propyn-1-ylamino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclopentylamino)-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(propylamino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(1R)-1-methylpropyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(2,2-Difluoroethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(phenylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(2-pyridinylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(4-pyridinylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(2-phenylethyl)amino]-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[({3-[(trifluoromethyl)oxy]phenyl}methyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(3-pyridinylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(2-methylphenyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(3-methylphenyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(4-methylphenyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide; 1,1-Dimethylethyl[7-ethyl-9-({[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]acetate;7-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]methyl}amino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;6-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5-trimethylhexyl)amino]propyl}-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-6-ethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1,3-dimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;N-[(1S,2R)-3-(Cyclohexylamino)-2-hydroxy-1-(phenylmethyl)propyl]-6-ethyl-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-3-({1-methyl-1-[3-(methyloxy)phenyl]ethyl}amino)-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(1,1,5-trimethylhexyl)amino]propyl}-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-3-[(1-methylethyl)amino]-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-3-({[3-(methyloxy)phenyl]methyl}amino)-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-3-{[(1-ethyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl]-1,3,3-trimethyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;N-[(1S,2R)-3-Amino-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-2-Hydroxy-3-(methylamino)-1-(phenylmethyl)propyl]-1-methyl-7-(1-methylethyl)-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-1-[(3-Chlorophenyl)methyl]-2-hydroxy-3-(methylamino)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-1-[(3-fluorophenyl)methyl]-2-hydroxy-3-(methylamino)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;6-Ethyl-N-[(1S,2R)-2-hydroxy-3-(methylamino)-1-(phenylmethyl)propyl]-1-methyl-1H-[1,2,5]thiadiazino[3,4,5-hi]indole-8-carboxamide2,2-dioxide;[7-Ethyl-9-({[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propyl]amino}carbonyl)-2,2-dioxido-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indol-1-yl]aceticacid;N-[(1S,2R)-3-{[(6-Bromo-2-pyridinyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-[({5-[(methylamino)carbonyl]-3-pyridinyl}methyl)amino]-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-[(2,2′-Bipyridin-6-ylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{([(6-methyl-2-quinoxalinyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-{(1S,2R)-2-hydroxy-1-(phenylmethyl)-3-[(3-quinolinylmethyl)amino]propyl}-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(6-methyl-2-pyridinyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-3-{[(5-ethyl-3-thienyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7-Ethyl-N-[(1S,2R)-2-hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;7Ethyl-N-[(1S,2R)-3-{[(3-ethyl-5-isoxazolyl)methyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide;N-[(1S,2R)-3-{[(1S)-2-(Cyclohexylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide; orN-[(1S,2R)-3-[(4,4-Difluorocyclohexyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide2,2-dioxide; or a pharmaceutically acceptable salt or solvate thereof.20. A pharmaceutical composition comprising a compound of formula (I) asdefined in claim 9 or a pharmaceutically acceptable salt or solvatethereof in admixture with one or more pharmaceutically acceptablediluents or carriers.
 21. A method of treatment or prophylaxis ofdiseases characterised by elevated β-amyloid levels or β-amyloiddeposits which comprises administering to a patient an effective amountof a compound of formula (I) as defined in claim 9 or a pharmaceuticallyacceptable salt or solvate thereof.
 22. A method according to claim 5,wherein the disease characterised by elevated β-amyloid levels orβ-amyloid deposits is Alzheimer's disease.